Two critical problems are associated with replicating paramyxo- and rhabdovirus vaccines expressing SARS-CoV-2 spike (S) protein such as VSVΔG(S). One is eliciting of potentially disease-enhancing non-neutralizing antibodies, the other the S-mediated spread in humans. In view of the multi-organ tropism of SARS-CoV-2 in humans, their pathogenic outcome is not predictable. Here, we address and resolve both issues. We describe an innovative VSV vaccine, which is safe both in terms of virus propagation and immune response, as it is a non-spreading single round replicon vector, and the immunogen is limited to the spike’s receptor binding domain (RBD), which emerged as the antigen eliciting the desired virus-neutralizing antibodies in humans. An excellent protective immune response in animals is achieved by the design of a chimeric RBD-minispike, which allows a combined “2-in-1” approach, meaning that the optimized antigen is simultaneously presented on cells and on noninfectious virus-like particles (VLPs). With such enhanced RBD antigen presentation it is thus not necessary to use replication-competent virus or entire S antigen.

IFNs constitute one of the first and most important innate immune controls to restrict initial viral replication and spread. As HIV has evolved mechanisms to block IFN-I induction in its target cells, but not in infiltrating pDCs, understanding how pDCs influence HIV infection of target cells upon initial transmission is critical to prevent or control initial infection. Therefore, we modelled the early events occurring immediately as HIV enters the human genital mucosa. We showed that IFNα secreting pDC compensated for HIV inhibition of IFN-I production in its target cells in two different ways: i) reduced infection in DCs and macrophages which would limit viral spread to resident or newly infiltrating memory CD4 T cells; ii) reactivation of latent HIV in all subsets of resting memory CD4 T cell subsets, accompanied by limited viral spread, upregulation of MHC-I and induction of a tissue retention phenotype. The increased HIV protein, MHC-I expression and retention may enhance exposure to CD8 T cell surveillance. This model suggests that IFNα reactivation of latent HIV combined with adoptive immunotherapy using CD8 T cells or those expressing chimeric antigen receptors (CAR) could provide a novel ‘kick and kill’ approach to eradicate HIV reservoirs.

The neutral glycosphingolipid globoside (Gb4) has been historically considered the cellular receptor of B19V, however, its wide expression profile does not correlate well with the restricted tropism of the virus. Here, we show that Gb4 is essential for the infection at a step following virus uptake and before the delivery of the viral ssDNA into the nucleus. B19V interacts with Gb4 exclusively under acidic conditions, prohibiting the interaction on the plasma membrane and promoting it inside the acidic endosomal compartments, which are engaged by the virus and the GSL after internalization. In the absence of Gb4, incoming viruses are retained in the endocytic compartment and the infection is aborted. This study reveals the mechanism of the interaction between the virus and the glycosphingolipid and redefines the role of Gb4 as an essential intracellular partner required for infectious entry.

Background

Hepatitis B virus (HBV) kills millions of people globally; it is worse in pregnant women. HBV and Human Immune Virus (HIV) co-infection is associated with increased liver diseases such as cirrhosis and hepatocellular carcinoma. This study aimed at identifying the determinants of HBV infection among HIV-positive pregnant women.

There are two widely used COVID-19 vaccination strategies; administering the two doses three to four weeks apart or delaying the administration of the second dose. A modelling study calibrated to COVID-19 spread and vaccination in the US shows that delaying the second dose can maximize the benefits of vaccination programs under certain conditions.

The genome of the flavivirus Zika virus is stuck in a tug-of-war between two directly opposing evolutionary pressures that are present in the cells of mammalian host organisms and mosquito vectors; this results in an adaptive compromise, as manifested in the virus’s genome dinucleotide composition.

Influenza vaccines are produced on a large scale to meet the annual U.S. and global demand. To efficiently produce the required number of influenza vaccine doses, virions are commonly used as the antigen source due to their high viral protein content. A draw-back to using virions is that the final antigen composition of the vaccine is determined by the inherent properties of the vaccine virus. While this approach for influenza vaccines is beneficial for the more abundant HA antigen, it likely limits the protective response generated by the less abundant NA antigen. Our results demonstrate that the NA and HA content in vaccine viruses can be optimized by changing the internal genes of the vaccine virus, thereby preserving the surface antigens. The increase in the virion NA content that was achieved elicited higher NA antibody titres and generated more balanced neutralizing antibody responses to HA and NA. Since HA and NA neutralizing antibodies are both protective, this approach could help to improve the suboptimal efficacy of current influenza vaccines and to generate vaccines that provide broader coverage against circulating strains.

Chagas’ disease is a neglected disease that afflicts over eight million individuals worldwide. Oxidative stress is an important cell response when infected by Trypanosoma cruzi, etiologic agent of Chagas disease, although its role in host cell DNA/RNA metabolism has not been fully described. In this study, we investigated how T. cruzi infection and oxidative stress affect DNA molecule and the host cell metabolism. Data show that T. cruzi infection promote oxidative stress, which induce protein oxidation and DNA damage in human cells. Interestingly, control of the oxidative stress reduces the parasite capacity of infection. Until now, drug treatment with Nifurtimox or Benznidazole (BNZ) is only effective in the acute phase of the disease. This work revealed that pre administered BNZ to the host cells was also efficient in reducing oxidative stress and DNA damage, caused by parasite infection. Therefore, BNZ could be preparing cellular metabolism to respond to T. cruzi infection also by controlling the oxidative stress that may be necessary for the parasite propagation.

FMDV is the causative agent of foot-and-mouth disease, one of the most contagious and economically devastating diseases of cloven-hoofed animals. The antigenic diversities of the currently known epitopes throughout FMDV serotypes and the lack of understanding of FMDV neutralization in natural hosts limit the development of a vaccine that is able to provide cross-serotype protection. In this work, we isolated FMDV serotype O-specific neutralizing antibodies (NAbs) (F145 and B77) and a serotype O/A cross-reacting NAb (R50) from recovered natural bovine hosts and determined virus-NAb complex structures by cryo-electron microscopy at near-atomic resolution. Structures of virus-NAb complex reveal F145 and B77 engage the capsid of FMDV-O near the icosahedral threefold axis. In contrast, R50 engages the capsids of both FMDV-O and FMDV-A between the 2- and 5-fold axes, revealing a previously unknown antigenic site. This is the first time to present structure details of FMDV neutralization by natural hosts. And this work also provides epitope information for the development of a universal vaccine for cross-serotype protection against FMDV.

Rationale/Study design

A major challenge in the development of HIV vaccines is finding immunogens that elicit protection against a broad range of viral strains. Immunity to a narrow range of viral strains may protect infants of HIV-infected women or partners discordant for HIV. We hypothesized that immunization to the relevant viral variants could be achieved by exposure to infectious virus during prophylaxis with antiretroviral drugs. To explore this approach in an animal model, macaques were exposed to live virus (SIV_mne or HIV-2₂₈₇) during prophylaxis with parenteral tenofovir and humoral and cellular immune responses were quantified. Subsequently, experimental animals were challenged with homologous virus to evaluate protection from infection, and if infection occurred, the course of disease was compared to control animals. Experimental animals uninfected with SIV_mne were challenged with heterologous HIV-2₂₈₇ to assess resistance to retroviral infection.

Though vaccination is generally considered effective in reducing tick-borne encephalitis (TBE) incidence, several studies have shown that the antibody response to TBEV vaccination declines with age resulting in more frequent TBE cases among 50+ year-old vaccinees. These observations together with the lack of a specific antiviral drug impose to pinpoint novel host- and pathogen-directed therapies and to improve the control of vaccine efficacy. Thus, we interrogated in vitro human PBMC, whose response to TBEV may provide a picture closer to what occurs in vivo in humans after vaccination or natural infection compared to animal models. The role of E glycoprotein and viral RNA in promoting antiviral and B cell-mediated responses was investigated. Thus, these key viral molecules should be considered, in future, for novel subunit vaccine formulations than the current whole inactivated TBEV-based vaccines, which require laborious manipulation in biosafety level-3 laboratory and animal testing for manufacturing and batch release.

Background

Although the approved COVID-19 vaccine has been shown to be safe and effective, mass vaccination in Bangladeshi people remains a challenge. As a vaccination effort, the study provided an empirical evidence on willingness to vaccinate by sociodemographic, clinical and regional differences in Bangladeshi adults.

Given their functions in cellular metabolism and immune responses, mitochondria are targeted and disrupted by numerous prevalent viral pathogens, including human cytomegalovirus (HCMV). To characterize mechanisms underlying mitochondrial regulation during HCMV infection in human fibroblasts, this study integrates enzyme-substrate interaction studies, mass spectrometry quantification of protein abundance and acetylation, mutagenesis, microscopy, and virology assays. These analyses establish a link between the mitochondrial acetylation status and mitochondrial structure and metabolism during HCMV infection. We demonstrate that the mitochondrial deacetylase SIRT3 acts in host defense by modulating proteins that regulate mitochondrial structure and fatty acid oxidation. SIRT3 helps to maintain mitochondrial integrity through several mechanisms, including regulation of mitochondrial pH, membrane potential, and the balance between mitochondrial fission and fusion. As excess mitochondrial acetylation is detrimental to mitochondrial metabolism, the virus-induced alterations in SIRT3 functions and mitochondrial acetylation may be linked to known HCMV pathologies, such as the metabolic syndrome and cardiac hypertrophy.

Background

The SARS-CoV-2 pandemic has forced health authorities across the world to take important decisions to curtail its spread. Genomic epidemiology has emerged as a valuable tool to understand introductions and spread of the virus in a specific geographic location.

SARS-CoV-2 has dramatically impacted Amerindian native communities across South America, particularly in the Amazonian basin. In order to unveil the introduction and initial spread of this pandemic virus into this region, we conducted a genomic epidemiology study where we sequenced 59 genomes from cases in the Amazonas department of Colombia. Our results showed two independent introductions of the virus into the department, one of these associated with asymptomatic cases. This represents the first genomic epidemiology study focused on the Colombian Amazonas department where a great amount of native Amerindian indigenous communities inhabits. Our results provide insights of the transmission dynamic in this region and reported relevant information to pursue strategies to mitigate the spread of the virus in the Amazon population which currently are facing new risks due to the circulating new variant of concern P.1.

Background

Scrub typhus is a neglected tropical disease that threatens more than one billion people. If antibiotic therapy is delayed, often due to mis- or late diagnosis, the case fatality rate can increase considerably. Scrub typhus is caused by the obligate intracellular bacterium, Orientia tsutsugamushi, which invades phagocytes and endothelial cells in vivo and diverse tissue culture cell types in vitro. The ability of O. tsutsugamushi to replicate in the cytoplasm indicates that it has evolved to counter eukaryotic host cell immune defense mechanisms. The transcription factor, NF-κB, is a tightly regulated initiator of proinflammatory and antimicrobial responses. Typically, the inhibitory proteins p105 and IκBα sequester the NF-κB p50:p65 heterodimer in the cytoplasm. Canonical activation of NF-κB via TNFα involves IKKβ-mediated serine phosphorylation of IκBα and p105, which leads to their degradation and enables NF-κB nuclear translocation. A portion of p105 is also processed into p50. O. tsutsugamushi impairs NF-κB translocation into the nucleus, but how it does so is incompletely defined.

Scrub typhus is a neglected disease that can be fatal and occurs predominantly in the Asia-Pacific, one of the most densely populated regions of the world. Notably, cases continue to emerge outside this area. The etiologic agent is Orientia tsutsugamushi, a bacterial pathogen that infects certain leukocytes and cells that line blood vessels in animals and humans. The success of O. tsutsugamushi to colonize these cells is at least partially attributable to its ability to counter host immunity. In this study, we demonstrate that O. tsutsugamushi stabilizes p105, a mammalian inhibitor of the transcription factor, NF-κB, which is otherwise key for activating proinflammatory and antimicrobial gene expression. O. tsutsugamushi is the first example of a bacterium that inhibits NF-κB by promoting elevated levels of p105 and impairing its degradation. Our findings provide fundamental information that helps explain how this important pathogen has evolved to stealthily establish infection in host cells.

Background

Despite decades of extensive research, bovine respiratory disease (BRD) remains the most devastating disease in beef cattle production. Establishing a clinical diagnosis often relies upon visual detection of non-specific signs, leading to low diagnostic accuracy. Thus, post-weaned beef cattle are often metaphylactically administered antimicrobials at facility arrival, which poses concerns regarding antimicrobial stewardship and resistance. Additionally, there is a lack of high-quality research that addresses the gene-by-environment interactions that underlie why some cattle that develop BRD die while others survive. Therefore, it is necessary to decipher the underlying host genomic factors associated with BRD mortality versus survival to help determine BRD risk and severity. Using transcriptomic analysis of at-arrival whole blood samples from cattle that died of BRD, as compared to those that developed signs of BRD but lived (n = 3 DEAD, n = 3 ALIVE), we identified differentially expressed genes (DEGs) and associated pathways in cattle that died of BRD. Additionally, we evaluated unmapped reads, which are often overlooked within transcriptomic experiments.

Objectives

This study evaluates the effect of Community Anti-retroviral Groups on Immunologic, Virologic and clinical outcomes of stable Antiretroviral Therapy patients in Nigeria.

The unfolded protein response (UPR) is a cellular response aiming to eliminate abnormal proteins in and restoring ER homeostasis. The infection of many plant viruses can induce the UPR of plant cells, and previous studies show that in most cases, the UPR benefits plant viral infections. However, how the UPR regulates plant viral infections is still poorly understood. Here, we find that a plant virus, rice stripe virus (RSV), can induce host UPR, and the UPR plays dual roles in RSV infection. On the one hand, the RSV-induced UPR activates the host autophagy pathway by which the virus-encoded movement protein, NSvc4, is degraded. On the other hand, the RSV-induced UPR also upregulates the expression of a type-I J-domain protein family in plant, which is hijacked by NSvc4 to protect itself from autophagic degradation. We present an example for an arms race between RSV and the host plant, and illustrate a new model of the UPR regulating viral infection in plants by fine-tuning the accumulation of virus-encoded MP.

Introduction

The Malawi Ministry of Health (MoH) has been in collaboration with Médecins sans Frontières (MSF) to increase access to quality HIV care through decentralization of antiretroviral therapy (ART) diagnosis and treatment from hospital to clinics in Nsanje District since 2011. A population-based household survey was implemented to provide information on HIV prevalence and cascade of care to inform and prioritize community-based HIV interventions in the district.

Background

The US National HIV/AIDS Strategy (NHAS) emphasizes the use of technology to facilitate coordination of comprehensive care for people with HIV. We examined cost-effectiveness from the health system perspective of 6 health information technology (HIT) interventions implemented during 2008 to 2012 in a Ryan White HIV/AIDS Program (RWHAP) Special Projects of National Significance (SPNS) Program demonstration project.

Starley Shade and co-workers assess cost-effectiveness of information technology interventions in HIV care programs in the United States.

Background

The prevalence of HCV infection is high and it is a major cause of liver-related morbidity and mortality in hemodialysis and renal transplant patients. Diagnosis of hepatitis C virus (HCV) infection requires both HCV antibody screening and confirmatory nucleic acid testing (NAT). Hepatitis C virus core antigen (HCVcAg) is a reliable direct viral marker to identify active HCV infection.

The devastating COVID-19 pandemic is caused by SARS-CoV-2, a novel virus that despite recent zoonotic introduction is already very well adapted to its human host. Its rapid spread is related to abundant replication in the upper airways, which is not observed for other highly pathogenic human coronaviruses. To understand the role of the viral spike protein in this airway adaptation, we constructed pseudoviruses of SARS-CoV-2 and other coronaviruses that cause severe pneumonia or, on the contrary, a mild common cold. The key findings were verified with authentic virus. We reveal features of the spike proteins, which optimize the coronavirus towards specific parts of the respiratory tract. Namely, we show that the spike proteins exhibit intrinsic temperature preference to precisely match the upper (~33°C) or lower (37°C) airways. We recognized which proteases of human airways activate the spike for virus entry, in particular one protease that may mediate coronavirus virulence. Finally, a link was perceived between spike stability and entry via endosomal proteases. We propose that these mechanisms of spike fine-tuning may have contributed to a global shift in SARS-CoV-2 epidemiology, from the early spike-D614 to the currently predominating G614 variant.

Introduction

The scale-up of Universal Test and Treat has resulted in reductions in HIV morbidity, mortality and incidence. However, healthcare system and personal challenges have impacted the levels of treatment coverage achieved. We implemented interventions to improve linkage to care, retention, viral load (VL) coverage and service delivery, and describe the HIV care cascade over the course of the Botswana Combination Prevention Project (BCPP) study.

RSV causes severe bronchiolitis in young children, is the leading cause of hospitalization of infants and a major cause of infant mortality in limited-resourced countries. In elders, it rivals influenza virus as a cause of death during the winter months. Many vaccines and antivirals are in development, but none has yet been approved. RSV targets ciliated cells in the upper and lower respiratory tracts. The use of primary HBE cultures previously enabled us to identify the target cell for RSV and a putative receptor on these cells, as well as to better understand the response to RSV infection, all in the cells it infects in vivo. Here, we found that RSV produced in these primary cultures contains a 170 kDa version of its attachment (G) glycoprotein that has lost most of its ability to infect the standard immortalized cell line used to culture RSV, HEp-2 cells, confirming that the receptor used on the two types of cells are different. These findings also demonstrate that significant structural differences with functional consequences can result from the type of cells used to produce the virus.

Despite widespread, effective use of ART among HIV infected pregnant women, new pediatric HIV infections increase by about 150,000 every year. Thus, alternative strategies will be required to reduce MTCT and eliminate pediatric HIV infections. Interestingly, in the absence of ART, less than half of HIV-infected pregnant women will transmit HIV, suggesting natural immune protection of infants from virus acquisition. To understand the impact of maternal plasma autologous virus neutralization responses on MTCT, we compared the plasma and bnAb neutralization sensitivity of the circulating viral population present at the time of delivery in untreated, HIV-infected transmitting and non-transmitting mothers. While there was no significant difference in the ability of transmitting and non-transmitting women to neutralize their own circulating virus strains, specific genetic motifs enriched in variants from transmitting mothers were associated with resistance to bnAbs, suggesting that acquired bnAb resistance is a common feature of vertically-transmitted variants. This work suggests that enhancement of plasma neutralization responses in HIV-infected mothers through passive or active vaccination could further drive selection of variants that could be vertically transmitted, and cautions the use of passive bnAbs for HIV-1 prophylaxis or therapy during pregnancy.

Understanding the evolution and transmission of SARS-CoV-2 is important for designing public health interventions to prevent outbreaks. Viral genome sequencing has been widely used to reconstruct patterns of SARS-CoV-2 transmission through communities and to monitor the spread of new strains. However, because SARS-CoV-2 can transmit multiple times before a new mutation fixes, consensus sequences often cannot determine “who infected whom.” Identifying individuals who share the same viral genetic variants at low frequencies within each infection may help resolve this problem, but to do this we need to accurately identify within-host genetic variants and understand how they evolve and spread. We investigated within-host diversity of SARS-CoV-2 with samples collected in southeastern Michigan in March–May 2020. We show that there are relatively few genetic variants present in any given infection, and variants do not tend to accumulate in people over time. We also found that people who are not part of the same epidemic cluster can share the same within-host variants, due to chance or various evolutionary forces.

Mayaro virus is an understudied alphavirus that is currently circulating in tropical environments in South and Central America without an approved vaccine. Recent outbreaks have suggested a broadening range and higher likelihood of urban outbreaks, increasing the public health risk. Mayaro virus is closely related to other arthritogenic alphaviruses with overlapping circulation such as chikungunya and Una viruses, both of which also lack clinically approved vaccines. Identification of a safe, easily manufactured, and effective strategy to vaccinate at risk populations is important to control outbreak potential. Here we report on a vaccination approach using a non-replicating adenovirus viral vector that encodes Mayaro virus structural proteins that assemble into non-infectious virus-like particles upon expression following vaccination. These particles stimulate strong immune responses against Mayaro virus. Upon testing against other alphaviruses, it was determined that the vaccine elicits cross-reactive neutralizing antibodies against chikungunya and Una viruses, significantly diminishes disease severity, and protects immunocompromised, highly susceptible mice from death following viral challenge. Our study provides new approaches to protect against these co-circulating viruses using a single vaccine. This approach is highly amenable to other virus targets for vaccine development and its ability to provide protection against chikungunya virus has global ramifications.

Introduction

New HIV infection during pre-conception and pregnancy is a significant contributor of mother–to–child transmission of HIV in South Africa. This study estimated HIV incidence (defined as new infection within the last one year from the time of the survey which included both new infections occurred during pregnancy or just before pregnancy) among pregnant women and described the characteristics of recently infected pregnant women at national level.

Little is known about the host response to Venezuelan Equine Encephalitis Virus (VEEV) and the cellular factors this alphavirus hijacks to support effective replication or evade cellular immune responses. Monitoring dynamics of host and viral RNA (vRNA) during viral infection at a single-cell level can provide insight into the virus-host interplay at a high resolution. Here, a single-cell RNA sequencing technology that detects host and viral RNA was used to investigate the interactions between TC-83, the vaccine strain of VEEV, and the human host during the course of infection of U-87 MG cells (human astrocytoma). Virus abundance and host transcriptome were heterogeneous across cells from the same culture. Subsets of differentially expressed genes, positively or negatively correlating with vRNA abundance, were identified and subsequently in vitro validated as candidate proviral and antiviral factors, respectively, in TC-83 and/or virulent VEEV infections. In the first replication cycle, “superproducer” cells exhibited rapid increase in vRNA abundance and unique gene expression patterns. At later time points, cells with increased structural-to-nonstructural transcript ratio demonstrated upregulation of intracellular membrane trafficking genes. Lastly, comparing the VEEV dataset with published datasets on other RNA viruses revealed unique and overlapping responses across viral clades. Overall, this study improves the understanding of VEEV-host interactions, reveals candidate targets for antiviral approaches, and establishes a comparative single-cell approach to study the evolution of virus-host interactions.

Dengue fever and dengue hemorrhagic fever in humans are caused by Aedes mosquito-mediated dengue virus infection. Large dengue outbreaks occurred in recent years and many tropical and subtropical countries became hyperendemic with all four dengue virus serotypes. We characterized the endemic dengue virus TW2015, which caused large outbreaks in Taiwan and Indonesia in 2015. Compared to other dengue viruses, the TW2015 virus was highly virulent in mice, with robust replication in spleen, lung, and intestine. The TW2015 virus had high transmissibility between mice and mosquitoes. The TW2015 structural genes that function in attachment of the virus particle to the cell surface during infection may be responsible for the high virulence of the virus in mice and its high transmissibility in mosquitoes. Our study revealed the key components of the dengue virus that contribute to its high likelihood of causing dengue outbreaks. These results will aid in the development of new approaches to prevent future dengue epidemics.

The temperature in the lower respiratory tract is higher than in the upper respiratory tract. This study compares the viral replication kinetics and host cell response during SARS-CoV-2 and SARS-CoV infection, finding that the temperature of the human respiratory epithelium influences the viral replication and virus-host dynamics of SARS-CoV-2, but not of SARS-CoV.

The generation and serial intervals are epidemiological quantities used to describe and predict an ongoing epidemic outbreak. These quantities are related to the contact pattern of individuals, since infection events can take place if infectious and susceptible individuals have a contact. Therefore, intervention measures that reduce the interactions between members of the population are expected to affect both the realized generation and serial intervals. For the current COVID-19 pandemic unprecedented interventions have been adopted worldwide, e.g. strict lockdown, isolation and quarantine, which influence the realized value of generation and serial intervals. The extent of the effect thereof depends on the efficacy of the control measure in place, on the relationship between symptom onset and infectiousness and on the proportion of infectious individuals that can be detected. To get more insight on this, we present an investigation that highlights the effect of quarantine and isolation on realized generation and serial intervals. In particular, we show that not only their variances but also their mean values can differ, suggesting that the use of the mean serial interval as a proxy for the mean generation time can lead to biased estimates of epidemiological quantities.

Human cytomegalovirus (HCMV) infection is usually asymptomatic in healthy individuals. However, newborns and immunocompromised patients are suffering from life-threatening diseases upon infection. After decades of research, vaccines are still not available and the use of antiviral therapeutics is limited. During the last years, drugs targeting the cellular DNA damage response (DDR) are increasingly applied in cancer therapy. Interestingly, HCMV utilizes the cellular DDR for its replication thereby implicating DDR components as promising targets for antiviral intervention. In this study, we found that the DDR enzyme flap endonuclease 1 (FEN1) is activated by the HCMV protein IE1 in a unique manner that depends on a direct protein-protein interaction. Moreover, we could demonstrate that FEN1, which is tremendously stabilized by IE1, supports efficient viral DNA replication. We propose a novel mechanism whereby a viral protein manipulates the cellular enzyme FEN1 to facilitate the multiplication of viral DNA genomes. Small molecule inhibitors of FEN1 might thus serve as a new antiviral therapy option.

We have developed an inactivated rabies virus vectored vaccine platform that has been used to develop a vaccine against SARS-CoV-2 (CORAVAX). CORAVAX induced high levels of neutralizing antibodies against SARS-CoV-2. Here we show that vaccinated hamsters, the best animal model for COVID-19, were protected against viral replication, indicating that this vaccine can stop transmission. CORAVAX also prevented lung disease. Rabies virus vaccines have been used in more than 100 million people worldwide, are safe and used in children and pregnant women. Therefore, it is anticipated that CORAVAX will generate robust immune responses against SARS-CoV-2 in humans that may also mimic the long-term protection seen in rabies vaccines.

Hopes for controlling SARS-CoV-2 rely on vaccination or infection to confer immunity that protects against subsequent infection. However, the “common-cold” seasonal coronaviruses re-infect people every few years. It has been unclear if these re-infections occur because immunity wanes rapidly, or because the virus evolves to escape immunity elicited by prior infection. Here we investigate the second hypothesis in the context of the common-cold coronavirus 229E. We test how well antibodies in old human sera neutralize both contemporaneous old 229E viruses, and more recent viruses that evolved after the sera was collected. We find that as 229E evolves, its spike protein accumulates mutations that escape neutralization by older human sera. The rate at which viral evolution degrades immunity varies among individuals, but in some cases less than a decade of evolution is sufficient to completely eliminate neutralization by human sera that is potent against contemporaneous viruses. Many of the viral mutations occur in the same regions of the spike (the RBD and NTD) that are changing in emerging variants of SARS-CoV-2. Therefore, our results suggest that coronavirus vaccines may need to be periodically updated to keep pace with viral evolution.

Ebola virus was responsible for several epidemics in the recent years and is now considered as a major public health concern in Central and West African countries. We and others demonstrated that pathogenic events observed during Ebola virus disease are linked to a deleterious immune response. However, the mechanisms implicated are not fully understood. Here, we studied immune responses depending on the viral loads observed in infected cynomolgus monkeys. An antiviral treatment allowed the reduction of viral load in some animals and we observed that these animals did not experience deleterious immune response and the loss of hemostasis. The release of pathogen-associated molecular patterns may thus be limited by the inhibition of viral replication, avoiding the overstimulation of the immune system and consequently the pathogenic events observed in Ebola virus disease.

Mutant sequences of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) arising during any individual case of coronavirus disease 2019 (COVID-19) could theoretically enable the virus to evade immune responses or antiviral therapies that target the predominant infecting virus sequence. However, commonly used sequencing technologies are not optimally designed to detect variant virus sequences within each sample. To address this issue, we developed novel technology for sequencing large numbers of individual SARS-CoV-2 genomic RNA molecules across the region encoding the virus surface proteins. This technology revealed extensive genetic diversity in cultured viruses from a clinical isolate of SARS-CoV-2, but lower diversity in samples from 7 individuals with COVID-19. Importantly, concurrent analysis of paired serum samples in selected individuals revealed relatively low levels of antibody binding to the SARS-CoV-2 spike protein at the time of initial sequencing. With increased serum binding to spike protein, we detected multiple SARS-CoV-2 variants bearing independent mutations in a single epitope, as well as a transient increase in virus burden. These findings suggest that SARS-CoV-2 replication creates sufficient virus genetic diversity to allow immune-mediated selection of variants within the time frame of acute COVID-19. Large-scale studies of SARS-CoV-2 variation and specific immune responses will help define the contributions of intra-individual SARS-CoV-2 evolution to COVID-19 clinical outcomes and antiviral drug susceptibility.

Background

Rotavirus vaccines have been adopted in African countries since 2009, including Mozambique (2015). Disease burden data are needed to evaluate the impact of rotavirus vaccine. We report the burden of rotavirus-associated diarrhea in Mozambique from the Global Enteric Multicenter Study (GEMS) before vaccine introduction.

Background

Rapid antigen tests hold much promise for use in the school environment. However, the performance of these tests in non-clinical settings and among one of the main target populations in schools—asymptomatic children—is unclear. To address this gap, we examined the positive and negative concordance between the BinaxNOW^™ rapid SARS-CoV-2 antigen assay and an RT-PCR test among children at a community-based Covid-19 testing site.

SARS-CoV-2 variants have appeared throughout the emergence of the current COVID-19 pandemic. In this study, characterization of a panel of infectious SARS-CoV-2 isolates in primary human respiratory cells allows the identification of important sequence features that contribute to virus replication.

Background

An appropriate specimen is of paramount importance in Real Time reverse transcription-polymerase chain reaction (rRT-PCR) based diagnosis of novel coronavirus (nCoV) disease (COVID-19). Thus, it’s pertinent to evaluate various diversified clinical specimens’ diagnostic utility in both diagnosis and follow-up of COVID-19.

Coronavirus encodes the conserved endoribonuclease nsp15, which has been reported to antagonize IFN responses by mediating evasion of recognition by dsRNA sensors. SGs are part of the host cell anti-viral response; not surprisingly, viruses in turn produce an array of antagonists to counteract such host response. Here, we show that IBV prevents the formation of SGs via nsp15, by reducing the accumulation of viral dsRNA, thereby evading the activation of PKR, phosphorylation of eIF2α, and formation of SGs. Depletion of SG scaffold proteins G3BP1/2 decreases IRF3-IFN response and increases the production of IBV. When overexpressed alone, nsp15s from different coronaviruses (IBV, PEDV, TGEV, SARS-CoV, and SARS-CoV-2) interferes with chemically- and physically-induced SGs, probably by targeting essential SGs assembly factors. In this way, coronaviruses antagonize the formation of SGs by nsp15, via reducing the viral dsRNA accumulation and sequestering/depleting critical component of SGs. To our knowledge, this is the first report describing the role of coronavirus nsp15 in the suppression of integral stress response, in crosstalk with anti-innate immune response.

During latent infection, gamma-herpesvirus genomes are maintained as extrachromosomal circular DNA, referred to as episomes, by dedicated viral-encoded episome maintenance proteins. KSHV-encoded LANA maintains viral episomes through binding as an oligomeric protein to repetitive DNA elements in the viral terminal repeats (TRs). Viral episomes can be visualized as LANA-associated nuclear bodies (LANA-NBs). Here, we show that LANA-NBs utilize mechanisms of self-assembly through liquid-liquid phase separation (LLPS) to build dynamic structures that change during cell cycle and viral life cycle. We find that DAXX is a component of the latent phase LANA-NBs, but is evicted during the transition to lytic replication where LANA remains associated with KSHV DNA to form a ring-like replication compartment.

However, no study has analyzed the association between antiretroviral therapy (ART) outcomes and pretreatment characteristics of patients with HIV/acquired immunodeficiency syndrome (AIDS) in Mongolia. This retrospective study aimed to determine the survival, CD4 T cell recovery, and immune reconstitution pattern during ART in HIV patients and to determine baseline patient characteristics associated with ART outcomes. Based on three different World Health Organization (WHO) guidelines, we analyzed the 3-year observation data of 166 patients with HIV/AIDS who received treatment between 2010 and 2017. An increase of >50 cells/μL indicated CD4 T cell count recovery, and a cell count of ≥500 cells/μL in patients with a baseline cell count of <500 cells/μL indicated immune reconstitution. In this study, the 3- and 1-year mortality rates were 5.4% (survival rate: 94.6%) and 3.6%, respectively. A total of 83% of deaths that occurred in the observation time occurred within the first 3 months. The CD4 T cell count recovery rates at 3, 12, and 36 months were 62.7%, 80.7%, and 89.2%, respectively. The CD4 T cell count increased to >500 cells/μL in 95 of 145 (65.5%) patients with a baseline cell count of <500 cells/μL after 36 months of ART. The baseline CD4 T cell count was found to be a sensitive indicator for immune reconstitution. An advanced pretreatment clinical stage of HIV infection (as classified by the WHO classification), a low CD4 T cell count in the peripheral blood, and a high viral load before the initiation of the first-line ART accurately predicted survival, CD4 T cell count recovery, and immune reconstitution in Mongolian patients with HIV/AIDS.

Introduction

Early infant diagnosis (EID) and treatment can prevent much of the HIV-related morbidity and mortality experienced by children but is challenging to implement in sub-Saharan Africa. Point-of-care (PoC) testing would decentralize testing and increase access to rapid diagnosis. The objective of this study was to determine the cost-effectiveness of PoC testing in Southern Province, Zambia.

Background

Neutralizing-antibody (nAb) is the major focus of most ongoing COVID-19 vaccine trials. However, nAb response against SARS-CoV-2, when present, decays rapidly. Given the myriad roles of antibodies in immune responses, it is possible that antibodies could also mediate protection against SARS-CoV-2 via effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), which we sought to explore here.

Dengue virus consists of four serotypes (DENV1-4) and there are different strains within a serotype. DENV can have smooth or bumpy surface morphologies at physiological body temperature of 37°C, depending on the strain. We have determined the cryoEM structures of a cross-reactive neutralizing human monoclonal antibody (HMAb) 1C19 in complex with strains of DENV1 and DENV2 that form either smooth or bumpy surface morphologies. We have mapped the epitope of HMAb 1C19 to E protein domain II and the epitope is likely partially hidden on the virus surface. We showed that the antibody has high affinity for binding to recombinant DENV1 E protein than to DENV2 E protein. This explains the strong neutralization activity for all DENV1 strains tested regardless of their morphologies at physiological temperature, whereas it can only neutralize DENV2 strain that exposes the epitope on the bumpy surface particles. These results suggest that high-affinity therapeutic antibodies could neutralize diverse dengue virus morphologies.

Background

Multidrug-resistant or rifampicin-resistant tuberculosis (MDR/RR-TB) and human immunodeficiency virus (HIV) co-infection are a deadly combination. While evidence on the effects of HIV co-infection on MDR/RR-TB treatment outcomes is well-documented, little published evidence describes the effects of MDR/RR-TB treatment on HIV disease.

Sample pooling consists in combining samples from multiple individuals into a single pool that is then tested using a unique test-kit. A positive test means that at least one individual within the pool is infected. Sample pooling could provide the means for rapid and massive testing for the presence of SARS-CoV2 among asymptomatic individuals. Here, we do not address any diagnostic problems—e.g. how to use a minimal number of tests to obtain an individual diagnostic—but rather focus on population-scale application of pooling. We first quantify the reduction of test sensitivity due to sample dilution and quantify the efficiency of large pools in (i) obtaining precise estimates of the proportion of infected individuals in the general population at reduced costs and (ii) implementing regular large-scale screenings beneficial in the early detection of epidemic outbreaks within communities (e.g. nursing homes or university campuses).

Background

Data on the national-level impact of pneumococcal conjugate vaccine (PCV) introduction on mortality are lacking from Africa. PCV was introduced in South Africa in 2009. We estimated the impact of PCV introduction on all-cause pneumonia mortality in South Africa, while controlling for changes in mortality due to other interventions.

Jackie Kleynhans and colleagues investigate whether introduction of the pneumococcal conjugate vaccine may have reduced all-cause pneumonia mortality in South Africa.

Background

Isolated or multi lineage cytopenia are the most common clinicopathological features and independently associated with increased risk of disease progression and death among human immunodeficiency virus infected children. In the study area, there is scarcity of data about the magnitude of various cytopenia.

Marek’s disease virus (MDV) is a highly contagious and oncogenic avian alphaherpesvirus that causes T-cell lymphomas in chickens. Alphaherpesviruses encoded U_S3 is a multifunctional protein kinase involved in viral replication, apoptosis resistance, and cell-to-cell spread. In this study, we evaluated the importance of MDV U_S3 in regulating MDV replication and pathogenesis in chickens. Our results provide first evidence that MDV U_S3 protein kinase is involved in the replication and pathogenicity of MDV in its natural host. We also identified chicken histone deacetylase 1 and 2 (chHDAC1 and 2) as novel substrates of U_S3 for MDV and characterized the potential impacts of MDV U_S3 induced phosphorylation in their protein stability, transcriptional regulation and protein interactions; to our knowledge, this is the first comparative study of the functions of U_S3 from all three MDV types. This is an important finding towards a better understanding of the functions of alphaherpesviruses encoded U_S3 protein kinase.

Hepatocellular carcinoma, the most common type of liver cancer, is the second leading cause of cancer death worldwide and is most commonly caused by hepatitis B virus infection. Currently, scientists have an incomplete understanding of the genomic basis of hepatocellular carcinoma associated with hepatitis B virus infection, because prior studies have been limited by imprecision in assessing hepatitis B virus infection status and heterogeneity in hepatitis B virus activity levels in liver tumors. This has limited scientists’ ability to devise new diagnostic and therapeutic options for hepatocellular carcinoma. In this study, we used computational genomics to directly measure hepatitis B virus RNA levels in a large dataset of hepatocellular carcinoma tumors, and found that tumors with measurable hepatitis B virus RNA levels are associated with a specific set of clinical and genomic characteristics. These characteristics have not previously been reported and harbor implications for future clinical and genomics research in hepatocellular carcinoma, as well as computational genomics efforts in other cancer types.

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated Coronavirus Disease 2019 (COVID-19) is a public health emergency. Acute kidney injury (AKI) is a common complication in hospitalized patients with COVID-19 although mechanisms underlying AKI are yet unclear. There may be a direct effect of SARS-CoV-2 virus on the kidney; however, there is currently no data linking SARS-CoV-2 viral load (VL) to AKI. We explored the association of SARS-CoV-2 VL at admission to AKI in a large diverse cohort of hospitalized patients with COVID-19.

Background

People living with human immunodeficiency virus (PLWH) are at risk of developing pulmonary hypertension (PH) and right ventricular (RV) dysfunction, but understanding of the relationship of RV function to afterload (RV-PA coupling) is limited. We evaluated the clinical and hemodynamic characteristics of human immunodeficiency virus (HIV)-associated PH.

IAV has evolved to exploit the host posttranslational modifications system for its own benefit. The transcription and replication of IAV genome occur in the nucleus of infected cells, which is catalyzed by the RNA-dependent RNA polymerase (RdRp). PB1 is the catalytic subunit and the assembly core of the RdRp. The ability to efficiently bind viral RNA by PB1 is a prerequisite for the RdRp to fulfil its function. In this study, we demonstrated that PB1 protein from different subtypes of IAV is a target of SUMOylation in both transfected and infected cells, and identified K612 of PB1 as the key SUMOylation site. The vRNP complex activity, replication in vitro, pathogenicity in mice and airborne transmission among ferrets were dramatically attenuated when the SUMOylation-defective PB1/K612R mutation was introduced. Notably, we found that SUMOylation at K612 is essential for PB1 to acquire the ability to efficiently bind viral RNA, thus allowing for the RdRp to transcribe and replicate the viral genome. Our findings therefore thoroughly explore the contribution of PB1 SUMOylation on influenza infection and establish SUMOylation site PB1 K612 as a potential target for anti-influenza drug development.

Background

Since COVID-19 pandemic is a global crisis, tests with high sensitivity and specificity are crucial for the identification and management of COVID-19 patients. There is an urgent need for low-cost rapid antigen COVID-19 test with a good diagnostic performance. Although various antigen rapid detection tests are widely available, strong evidence of their usefulness in clinical practice are still limited. Therefore, our aim was to evaluate clinical performance of STANDARD Q COVID-19 Ag Test (SD Biosensor, Gyeonggi-do, South Korea).

Despite much effort, an effective vaccine against HIV/AIDS has not been developed. There are many obstacles that continue to undermine this effort, which is focused largely on inducing neutralizing antibodies that can protect against infection. We conducted a pre-clinical vaccine study in nonhuman primates that utilized a trimeric HIV-1 envelope vaccine to induce neutralizing antibodies. We found that all animals that developed very high levels of neutralizing antibodies were protected against infection. When we mapped the neutralizing antibody responses using viral mutants, we found that they mainly targeted one exposed region of the HIV-1 envelope protein that is unique to the strain we used in the vaccine. By isolating individual antibodies from a protected animal with a very high level of neutralizing antibodies, we found that an expanded antibody family was responsible for the neutralization. Our findings demonstrate that neutralizing antibodies targeting mainly one exposed region on the envelope trimer vaccine were associated with protection, and that this could be achieved by a single antibody family that develops and expands during immunization.

Background

Hepatitis B virus (HBV) is a highly contagious pathogen that has become a severe public health problem and a major cause of morbidity and mortality, particularly in developing countries. Medical students are at high occupational risk during their training. However, no facility-based studies were found among medical students in eastern Ethiopia. Thus, this study aimed to investigate the seroprevalence of Hepatitis B Virus and associated factors among medical students in eastern Ethiopia.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever with a high case-fatality rate (approximately 5% to >40%). Indigenous SFTS has been reported in China, Japan, South Korea, and Vietnam. Thus, the development of an effective vaccine for SFTS is urgently needed. Vaccinia virus (VAC) was previously used as a vaccine for smallpox. Unfortunately, after these strains, the so-called second generation of VAC used during the eradication campaign was associated with severe adverse events, and the third generation of VAC strains such as LC16m8 (m8) and modified vaccinia Ankara (MVA) was established. m8 is confirmed to be highly attenuated while still maintaining immunogenicity. m8 is licensed for use in healthy people in Japan. At the present time, approximately 100,000 people have undergone vaccination with m8 without experiencing any severe postvaccine complications. At present, third-generation VAC strains are attractive for a recombinant vaccine vector, especially for viral hemorrhagic infectious diseases, such as Ebola virus disease, Lassa fever, Crimean-Congo hemorrhagic fever, and SFTS. We investigated the practicality of an m8-based recombinant vaccine for SFTS as well as other promising recombinant VAC-based vaccines for viral hemorrhagic infectious diseases.

Dr Sylvia Gardner first discovered the BK polyomavirus (BKPyV) in the urine of a kidney-transplant recipient in 1970. In the 1990’s, the widespread use of potent immunosuppressive drugs such as tacrolimus, sirolimus or mycophenolate mofetil led to the emergence of BKPyV nephropathy. Recently, various studies reported a specific influx of myeloid dendritic cells (mDCs) in the renal tissue of kidney-transplant patients who were diagnosed with a BKPyV nephropathy. MDCs are immune cells both residing in tissues and migrating to other organs or compartments like the blood when changes in their environment occur. Their main functions are the detection of danger signals such as pathogens or tumors and the processing of antigens to prime naïve specific effectors of the adaptive immune response. Although anti-BKPyV cellular immune responses have been investigated in post-transplant recipients as well as healthy individuals, supporting an active role of mDCs little is known about how mDCs and BKPyV interact with each other. Our study provides the basis to understand the role played by mDCs in virus capture through an unprecedented endocytic mechanism and possibly in viral protection from neutralization by specific antibodies. Moreover, we showed that mDCs are unable to sense BKPyV particles or BKPyV-infected dying cells as a danger signal, supporting the view that other DC subsets might act as the true antigen presenting cells that promote the adaptive immune response against BKPyV infection.

Filoviruses are among the deadliest pathogens known to mankind with case-fatality rates ranging from 25–90%. New outbreaks in central Africa and the identification of novel filoviruses in other regions highlight the urgent need to develop novel therapeutics. Although many novel anti-filovirus compounds have been reported as entry inhibitors, to date, none have made to market. This high rate of failure is in part due to a lack of knowledge of the mechanisms of action. In this report, we provide a molecular basis for the multiple mechanisms of action by which small molecule inhibitors of Ebola virus and Marburg virus block virus entry, which provides new mechanistic insight to guide design for next-generation viral entry inhibitors.

Background

With the introduction of effective antiretroviral therapy (ART), people living with HIV (PLWH) are surviving longer and are at risk for developing metabolic abnormalities that contribute to cardiovascular disease (CVD). In Sub-Saharan Africa (SSA), there is a paucity of epidemiological data on lipid profiles among young adults receiving ART. This study aimed to estimate the prevalence of low high-density lipoprotein cholesterol (HDL-c), a cardioprotective lipid class, and whether it differed by age among adults on ART in Livingstone, Zambia.

Background

Two automatable in-house protocols for high-troughput RNA extraction from nasopharyngeal swabs for SARS-CoV-2 detection have been evaluated.

Introduction

The global abrupt progression of the COVID-19 pandemic may disrupt critical life-saving services such as routine immunization (RI), thus increasing the susceptibility of countries to outbreaks of vaccine-preventable diseases (VPDs). Being endemic to several infectious diseases, Lebanon might be at increased risk of outbreaks as the utilization of RI services might have deteriorated due to the pandemic and the country’s political unrest following the October 2019 uprising. The aim of this study was to assess the changes in the utilization of RI services in both the public and private sectors following the COVID-19 pandemic.

Background

Older adults represent 70–90% of seasonal influenza-related deaths and 50–70% of influenza-related hospitalizations. Vaccination is the most efficient means of preventing influenza and reducing influenza-related illnesses. We aimed to describe knowledge, attitudes, and practices (KAP) of seasonal influenza vaccination among older adults in Honduras.

Although the immune system is critical for controlling herpes simplex virus (HSV) infection in the central nervous system (CNS), a prolonged or excessive immune response may be harmful. We studied the contribution of inflammasomes, innate immune proteins that initiate a pro-inflammatory response, to detrimental neuroinflammation in a murine model of herpes simplex encephalitis (HSE). We found that inflammasomes that rely on the adaptor protein ASC contribute to mortality and neuroinflammation independent of controlling viral replication. Additionally, we demonstrate that the inflammasome response to HSV is primarily mediated by microglia and leads to an influx of macrophages in the CNS. These results provide insights into the mechanisms that drive pathogenic inflammation in HSE and suggest a promising therapeutic target in treating HSE.

Background

Antibiotic resistance is a leading global public health concern and antibiotic use is a key driver. Effective interventions are needed to target key stakeholders, including general practitioners (GPs). In Malta, little is known about factors that influence GPs’ antibiotic prescribing, making it challenging to implement targeted interventions. We therefore aimed to explore GPs’ understanding of antibiotic use and resistance, and describe their perceived barriers and facilitators to prudent antibiotic prescribing for acute respiratory tract infections in Malta.

Vaccinia virus (VACV) is a large DNA virus with an acute and increasing demand for energy and macromolecules to build hundreds and thousands of viral particles in a single cell within hours of infection. The demand postulates reprogramming of the TCA cycle, as it is the central metabolic hub of a cell that generates metabolites for energy production and macromolecule synthesis. We show that VACV infection reprograms cellular metabolism globally, elevating the TCA cycle intermediate levels and modulating related cell metabolism. The elevation of the TCA cycle intermediates depends on the virus-encoded growth factor that stimulates non-canonical STAT3 signaling during VACV infection. Our results provide the metabolic foundation of viral growth factor to boost VACV infection.

Live attenuated virus vaccines are among the most effective interventions to combat viral infections. Historically, the mechanism of attenuation has involved genetically reducing the viral growth rate, often achieved by adapting the virus to grow in a novel condition. More recent attenuation methods use genetic engineering but also are thought to impair viral growth rate. These classical attenuations typically result in a tradeoff whereby attenuation depresses the within-host viral load and pathology (which is beneficial to vaccine design), but reduces immunity (which is not beneficial). We use models to explore ways of directing the attenuation of a virus to avoid this tradeoff. We show that directed attenuation by interfering with (some) viral immune-evasion pathways can yield a mild infection but elicit higher levels of immunity than of the wild-type virus.

The host immune response to herpesviruses includes intrinsic immunity, which is a constitutively active line of defense. Members of the Tripartite Motif (TRIM) superfamily of proteins, such as cytoplasmic TRIM5α and nuclear TRIM19, are examples of such restriction factors against the prototypical α-herpesvirus, herpes simplex virus-1 (HSV-1). Previous reports on the antiviral function of the protein encoded by TRIM22, a gene closely related to the TRIM5 gene, emphasized its antiretroviral role. We show that TRIM22 has an additional role as a restriction factor against herpesviruses. We found that TRIM22 inhibits a mutant form of HSV-1, by promoting chromatin compaction of the viral DNA encoding immediate-early viral genes–this consequently inhibits viral replication and reduces virus yields. Unlike other restriction factors that are degraded by the viral infected cell polypeptide 0 (ICP0), TRIM22 is not degraded by ICP0. We also show that TRIM22 inhibits representative members of the β-herpesvirus (cytomegalovirus) and γ- herpesviruses (Epstein-Barr virus). In addition, different TRIM22 genetic variants show differing levels of HSV-1 inhibition. Together, these results argue for the importance of the TRIM22 gene as a restriction factor against herpesviruses, and offer a novel avenue for further investigation on the role of TRIM genes in host genetic variation in herpesviral susceptibility.

Each Gc-protein with amino acid deletions within the “hot spot” of mutations failed to react with any neutralizing anti-SBV monoclonal antibodies or a domain specific antiserum. In addition, in vitro virus replication of the natural deletion variant could not be markedly reduced by neutralizing monoclonal antibodies or antisera from the field. The large-deletion variant of SBV that could be isolated in cell culture was highly attenuated with an impaired in vivo replication following the inoculation of sheep.

In conclusion, the observed amino acid sequence mutations within the N-terminal main immunogenic domain of glycoprotein Gc result in an efficient immune evasion from neutralizing antibodies in the special environment of a developing fetus. These SBV-variants were never detected as circulating viruses, and therefore should be considered to be dead-end virus variants, which are not able to spread further. The observations described here may be transferred to other orthobunyaviruses, particularly those of the Simbu serogroup that have been shown to infect fetuses. Importantly, such mutant strains should not be included in attempts to trace the spatial-temporal evolution of orthobunyaviruses in molecular-epidemiolocal approaches during outbreak investigations.

Schmallenberg virus (SBV) is a pathogen of veterinary importance and is used as a model virus for studying peribunyaviruses, a complex and highly divergent family of RNA viruses. An SBV-infection of naïve dams during pregnancy may lead to the induction of severe malformation in the fetus. In the medium (M) genomic segment of SBV and related viruses, a region of high sequence variability was detected, affecting the N-terminal major immunogenic domain of envelope protein Gc in malformed fetuses. Variation of this mutation hot spot in fetuses was demonstrated to result in immune-evasion from neutralizing activity in the infected fetus. Accordingly, the neutralization capacity of SBV-specific antisera collected from SBV-infected animals on the in vitro growth of such a variant virus isolate was severely impaired. Furthermore, the deletion mutant was attenuated for adult sheep. This study provides important new insights into the mechanisms of virus persistence within chronically infected malformed fetuses and explains the mystery of the “hot-spot” of sequence variations not only observed in SBV, but also in related viruses. The model proposed can represent an example of virus mutations resulting in antibody induced immune escape.

Introduction and aim

Comorbidities and comedication are common in patients with hepatitis C, which could result in a risk of drug-drug interaction. The objective of this study was to evaluate the prevalence of comorbidities, comedication and drug-drug interactions involving direct-acting antivirals in this population.

Introduction

Several methods have been proposed to estimate the time of HIV seroconversion, including those based on CD4 cell depletion models. However, previous models have failed to consider the heterogeneity that exists in CD4 trajectories among different sub-populations. Our objective was to estimate the time from HIV seroconversion relative to the HIV diagnosis date in a population-based cohort of people living with HIV (PLWH) in the province of British Columbia, Canada.

In 2013, H7N9 influenza viruses appeared in China and other countries resulting in 1, 567 human infections and 615 deaths. Understanding the cross-talk between virus and host is vital for the development of effective vaccines and therapeutics. Here, we identified the PB1 protein of H7N9 virus as a novel negative regulator that enhances the degradation of MAVS, an essential adaptor protein in the innate signaling pathway. Mechanistically, PB1 promoted the E3 ligase RNF5-mediated ubiquitination of MAVS and recruited the selective autophagic receptor NBR1 to associate with and deliver the ubiquitinated MAVS to the autophagosomes for degradation. Thus, the PB1-RNF5-MAVS-NBR1 axis inhibited innate immune antiviral response and facilitated virus replication by mediating MAVS degradation in an autophagosome-dependent manner. Our findings reveal a novel mechanism by which influenza virus negatively regulates the innate immune response.

SARS-CoV-2 infects the respiratory tract, targeting cells of the diverse airway epithelium. Infection outcomes depend on several factors that may vary in this heterogenous population including viral tropism, antiviral immunity, and response to antiviral therapies like remdesivir. We found that SARS-CoV-2 infects an array of airway epithelial cells, relying on the host protease TMPRSS2 for entry. Ciliated epithelial cells were the dominant target, and remdesivir blocked viral replication across multiple cell types. We uncovered cellular heterogeneity in early antiviral immunity to SARS-CoV-2 and identified cell type-specific ISGs associated with either high levels of viral replication or protection from infection.

A key epidemiological variable characterizing the spread of an infectious disease is the generation time, defining the time between successive cases in a chain of transmission. Although there is increasing evidence supporting a prolonged viral shedding window for COVID-19, it is currently unclear to what extent prolonged transmission also occurs. Here we investigate the plausibility of a population of chronically infected individuals who can stay infectious for a longer duration than the reported generation time, but with infectivity reduced to varying degrees. By using the daily case and fatality data from various countries, we show that the existence of a chronically infected population is not a possibility that can be easily rejected from an epidemiological perspective. Moreover, in case of a gradual easing on the lockdown measures, the predictions of the model including the chronically infected population vary considerably from the predictions of the conventional epidemiological models. Although it is not possible to either prove or disprove the existence of a hypothetical population purely by modeling, our results provide tentative evidence to consider a chronically infected population as an alternative modeling approach in assessing the transmission dynamics of COVID-19.

Cytomegalovirus (CMV) is a common cause of disease in immune compromised individuals as well as a common cause of congenital infections leading to disease in newborns. The virus is thought to enter primarily via mucosal barrier tissues, such as the oral and nasal mucosa. However, it is not clear how the virus escapes these barrier tissues to reach distant sites. In this study, we used a mouse model of CMV infection. Our data illustrate a complex balance between the immune system and viral infection of “myeloid cells”, which are most commonly thought to carry the virus around the body after infection. In particular, our data suggest that robust immune responses at the site of infection force the virus to rely on myeloid cells to escape the site of infection. Moreover, viral genes designed to evade these immune responses were needed to protect the virus during and after its spread to distant sites. Together, this work sheds light on the mechanisms of immune control and viral survival during CMV infection of mucosal tissues and spread to distant sites of the body.

Kaposi’s sarcoma–associated herpesvirus (KSHV), a member of the gammaherpesvirus subfamily, is associated with the pathogenesis of various tumors. Poly(ADP-ribose) polymerase 1 (PARP1), which is involved in various cellular functions, restricts lytic replication of oncogenic gammaherpesviruses by inhibiting replication and transcription activator (RTA), a molecular switch that activates the viral lytic replication. To abrogate the inhibitory effect of PARP1, reactivated KSHV promotes PARP1 degradation via direct interaction between PARP1 and PF-8, a viral processivity factor. Dimerization domains of PF-8 were found to be critical for PARP1 interaction and degradation and for enhancing the RTA transactivation activity. Furthermore, we found that CHFR, an E3 ubiquitin ligase, is required for PF-8–induced PARP1 degradation and efficient lytic replication of KSHV. This is the first study to show the role of CHFR in viral replication or pathogenicity. This study revealed a molecular mechanism via which gammaherpesviruses overcome the PARP1-mediated inhibitory effect on viral replication: by means of PF-8, which recruits a cellular E3 ubiquitin ligase.

We used a screen of genetically diverse mice from the Collaborative Cross infected with mouse-adapted SARS-CoV in combination with comprehensive pre-infection immunophenotyping to identify baseline circulating immune correlates of severe virologic and clinical outcomes upon SARS-CoV infection.

Ae. albopictus is an important vector of arboviruses such as dengue and Zika viruses. Studies on virus-host interaction at gene expression and molecular level are crucial especially in devising methods to inhibit virus replication in Aedes mosquitoes. Previous reports have shown that, besides protein-coding genes, noncoding RNAs such as lncRNAs are also involved in virus-host interaction. In this study, we report a comprehensive catalog of novel lncRNA transcripts in the genome of Ae. albopictus. We also show that the expression of lncRNAs was altered upon infection with dengue and Zika. Additionally, depletion of certain lncRNAs resulted in increased replication of dengue and Zika; hence, suggesting potential association of lncRNAs in virus infection. Results of this study provide a new avenue to the investigation of mosquito-virus interactions, especially in the aspect of noncoding genes.

Background

Sexual transmission chains of Ebola virus (EBOV) have been verified and linked to EBOV RNA persistence in semen, post-recovery. The rate of semen persistence over time, including the average duration of persistence among Ebola virus disease (EVD) survivors, is not well known. This cohort study aimed to analyze population estimates of EBOV RNA persistence rates in semen over time, and associated risk factors in a population of survivors from Sierra Leone.

Intracellular pathogens modulate host cell actin cytoskeleton by secreting an array of effector molecules to ensure their cell invasion and intracellular survival. The zoonotic pathogen Bartonella spp trigger massive F-actin polymerization of host cells resulting the internalization of large bacterial aggregates (called “invasome” structure), which is dependent on a functional VirB/VirD4 type IV secretion system (T4SS) and its translocated Bep effector proteins. Here, we have used cell infection and ectopic expression assay to identify that Bartonella T4SS effector BepC induces stress fiber formation in infected host cells. However, BepC also disrupts the balance of stress fiber formation and focal adhesion maturation, and eventually causes cell fragmentation. Using immunoprecipitation and RNAi approaches, we identify GEF-H1 is the host factor targeted by BepC. Interaction with BepC induces the release of GEF-H1 from microtubules to plasma membrane and subsequently activates RhoA-ROCK to induce stress fiber formation. These findings shed light on our understanding of how Bartonella invade host cell and establish infection.

SARS-CoV-2 uses its spike (S) protein to enter target cells. Unlike other similar coronaviruses, the nascent S protein has a polybasic cleavage motif and is cleaved by the host protease. We have identified SARS-CoV-2 variants with mutations at the cleavage motif of S protein (S gene mutants) which undergo inefficient proteolytic cleavage, generate smaller plaques, and infect fewer cell lines. Notably, S gene mutants emerged rapidly through SARS-CoV-2 propagation in Vero cells. Since Vero cells are commonly used for SARS-CoV-2 propagation, it is a very real possibility that researchers have performed experiments, screened antivirals, and developed vaccines using SARS-CoV-2 S gene mutants without realizing.

Host-pathogen conflicts leave genetic signatures in genes that are critical for host defense functions. This study uses these “molecular scars” as a guide to identify a vertebrate-specific mitochondrial stress response circuit that interacts with the electron transport chain and is activated by stress signals such as interferon-gamma and hypoxia.

Introduction

It has been estimated that between 15% and 18% of patients who start antiretroviral therapy (ART) do not achieve a successful immune recovery despite complete virological suppression. In the literature this phenomenom is known as poor immune recovery or immunovirological discordance (IVD). Zinc has an immunomodulatory role associated with T lymphocytes and its supplementation could enhance immune recovery.

Background

Vascular leak is a hallmark of severe dengue, and high leukotriene levels have been observed in dengue mouse models, suggesting a role in disease pathogenesis. We sought to explore their role in acute dengue, by assessing levels of urinary LTE4 and urinary histamine in patients with varying severity of acute dengue.

Cell surface glycans, including histo-blood group antigens (HBGA) and sialic acids (SAs), have been shown to serve as receptors/attachment factors for many pathogens including RVs. However, how those glycans affect RV replication remains largely unknown due the lack of reliable in vitro models. To solve this problem, we established a 3D porcine intestinal enteroid (PIE) model that recapitulates the complex intestinal morphology better than conventional cell lines. By utilizing PIEs expressing different types of HBGAs, we found that several RV strains including Wa G1P[8], OSU G5P[7] and G9P[13] show preference for certain HBGA types. Interestingly, only Wa replication was reduced when HBGAs synthesis was inhibited, while that of OSU and G9P[13] was only marginally affected, which indicates that they may utilize alternative attachment factors for infection. Sialidase treatment strongly inhibited the growth of OSU, while G9P[13] replication was significantly enhanced. These findings suggest that SAs play contrasting roles in the infection of PRV OSU and G9P[13] strains. Overall, our studies demonstrate that PIEs can serve as a model to study pathogen-glycan interactions and suggest that genetically distinct RVs have evolved diverse mechanisms of cell attachment and/or entry.

Bacterial pathogens have evolved a repertoire of diverse effector proteins that are secreted or injected into the host cell cytosol, reprogramming the host cell into a more favorable environment. Many of these pathogens possess nuclear-targeted effector proteins (nucleomodulins) that modulate host cell gene expression without altering the cellular genomic sequence. By utilizing nucleomodulins obtained through evolution, pathogens can manipulate host cell gene regulation and alter host immune response to infection. Here, we provide a comprehensive review discussing a diverse array of nucleomodulins that target and modulate the host genome through interference with chromatin dynamics, histone modifications, regulation of transcription, interference of the cell cycle, and regulation of cell signaling pathways for immune response. This unique targeting of host cell gene regulation through bacterial nucleomodulins is an emerging theme and likely the tip of an iceberg regarding host–pathogen interactions at the level of the host command center.

Hepatitis B virus (HBV) causes acute and chronic viral hepatitis, liver fibrosis, cirrhosis and cancer. The dynamic phosphorylation and dephosphorylation of the viral capsid protein (HBc), which are controlled by host cell protein kinases and phosphatases, play a critical role in regulating multiple stages of HBV replication. While a number of cellular kinases have been identified that mediate HBc phosphorylation, there is little information on cellular phosphatases that mediate its dephosphorylation. Herein we have identified a consensus binding motif in HBc for one of the major cellular phosphatases, the protein phosphatase 2A (PP2A). Genetic analysis of this motif revealed that it played multiple roles in regulating CTD phosphorylation state, as well as viral RNA packaging, reverse transcription, virion secretion, and formation of the nuclear HBV episome responsible for viral persistence. Furthermore, pharmacological inhibition of PP2A decreased HBc dephosphorylation and increased the nuclear episome, further supporting a role of PP2A in HBc dephosphorylation and HBV persistence. These results thus suggest that HBc recruits PP2A, among other host factors, to regulate HBc phosphorylation and dephosphorylation dynamics and HBV replication and persistence.

Background

Ethiopia launched the Health Extension Program (HEP) in 2004, aimed at ensuring equitable community-level healthcare services through Health Extension Workers. Despite the program’s being a flagship initiative, there is limited evidence on whether investment in the program represents good value for money. This study assessed the cost and cost-effectiveness of HEP interventions to inform policy decisions for resource allocation and priority setting in Ethiopia.

HIV-1 Env glycoprotein is produced by a precursor gp160 that has a signal peptide at its N-terminus. The SP is highly diverse among the HIV-1 isolates. This study presents site-specific analyses of N-linked glycosylation on HIV-1 envelope glycoproteins from infectious viruses produced with different envelope signal peptides. We show that signal peptide swapping alters the envelope glycan shield, including the conserved N156 and N160 glycans located in the V1V2 region on the trimer apex, to impact Env recognition and virus neutralization by antibodies. The data offer crucial insights into the role of signal peptide in the interplay between HIV-1 and antibodies and its potential utility to control Env glycosylation in the development of Env-based HIV-1 vaccine.

Background/Aims

Undetectable HCV RNA 12 weeks after the end of treatment (SVR12) has been the valid efficacy endpoint in the era of direct-acting antivirals (DAAs). Its concordance with SVR4 and SVR24 and long-term durability is unknown in Taiwanese chronic hepatitis C (CHC) patients.

Background

While the proportion of HIV-positive children (under 15 years) enrolled on antiretroviral therapy (ART) has increased in recent years, up to 60% of children started on ART do not achieve virological suppression. We set out to determine the factors associated with virological non-suppression among children living with HIV receiving ART at a peri-urban HIV care clinic in Kampala, Uganda.

Poxvirus vector systems have been widely developed for vaccine applications. Despite considerable progress, so far only one recombinant poxvirus vectored vaccine has to date been licensed for human use, with ongoing efforts seeking to enhance immunogenicity whilst minimizing reactogenicity. The latter two characteristics are often determined by early post-vaccination events at the injection site. We therefore undertook an injection site vaccinology approach to analyzing gene expression at the vaccination site after intramuscular inoculation with a recombinant, multiplication defective, vaccinia-based vaccine. This provided detailed insights into inter alia expression of vector-encoded immunoregulatory genes, as well as host innate and adaptive immune responses. We propose that such injection site vaccinology can inform rational vaccine vector design, and we discuss how the information and approach elucidated herein might be used to improve immunogenicity and limit reactogenicity of poxvirus-based vaccine vector systems.

In this review, we examine the current state of nuclear architecture in infectious diseases with an emphasis on chromosomal reorganization. Nuclear architecture plays an important role in regulation of transcription for several pathogens, as well as inflammatory responses in their host. Recent advances in technologies such as Hi-C have allowed in-depth studies of chromosomal reorganization during infectious disease development and provided insights into transcription mechanisms and pathogenicity. In addition, it has been demonstrated that pathogens can also affect/utilize the hosts nuclear architecture. These areas are heavily understudied in pathogens, and we hope this review will provide a comprehensive review on the current state of nuclear architecture in infectious diseases and provide an additional avenue for eradication efforts.

Host heterogeneity in pathogen transmission presents a major hurdle to predicting and minimizing the spread of infectious agents. Part of the difficulty in linking individual variation to epidemic outcomes is that individual hosts can vary on multiple behavioral, physiological, immunological axes that may affect their transmission potential. Moreover, we lack well-characterized empirical systems that allow to measure multiple facets of individual variation in pathogen transmission. In this work, we capitalize on the strengths of the fruit fly Drosophila as an established and powerful model system for genetics, behavior, and immunity. We provide individual-level data on several axes of infection and test how each of these components experiences variation arising from host genetic background, sex, and mating status. We are therefore able to identify the sources of host heterogeneity (i.e., genetic background, sex) and the specific host traits (social aggregation, pathogen shedding, infection duration) that are most important in determining disease dynamics. We find that a substantial proportion of between-individual heterogeneity in disease transmission is explained by genotype-by-sex interactions affecting the likelihood that individuals will shed virus, but also how much they are likely to shed.

Background

Broad community acceptance of a COVID-19 vaccination will be critical for effectively halting the spread of the virus. In this study, we focus on factors that differentiate those who are undecided from those who are either willing or unwilling to accept a prospective COVID-19 vaccine.

The flexible life cycle of the intracellular parasite Toxoplasma gondii allows it to infect many different types of warm-blooded hosts, as well as diverse cell types once inside the host organism. This formidable achievement is partly mediated by the establishment of a unique compartment following host cell invasion, termed the parasitophorous vacuole. While advancements have been made in cataloguing Toxoplasma secreted proteins that reside within this vacuole, the specific functions and contributions of many of these secreted parasite “tools” remain elusive. Here, we assessed the contribution of a parasite vacuolar protein called TgPPM3C, predicted to function as an enzyme that dephosphorylates other proteins. We found that deleting the TgPPM3C gene in the parasite results in a profound virulence defect during infection in mice, likely due to the dysregulated phosphorylation status of many vacuolar proteins detected by phosphoproteomic analysis of TgPPM3C-deleted parasites. We found that the phosphorylation status of one such protein, GRA16, influences its ability to cross the parasitophorous vacuole membrane and enter the host cell, where it is known to induce host transcriptional changes that benefit parasite growth. These findings illustrate the emerging role of Toxoplasma vacuolar phosphatases in regulating host-parasite interactions during infection.

Usutu virus (USUV) infection impairs eIF2α phosphorylation and SGs assembly, in an oxidative stress related manner, as a mechanism to evade cellular stress response. Our results provide new insights into the complex connections between the stress response and USUV infection to maintain a better cellular environment for viral replication.

Picornaviruses are important pathogens but their assembly is incompletely understood, preventing development of anti-viral drugs and vaccines. We report identification of multiple RNA stem–loops, with purine trinucleotide sequence motifs in each loop, distributed across the genomes of two enteroviruses, enterovirus-E and poliovirus. Each motif appears to have affinity for its cognate capsid protein. Cryo-EM reconstruction of enterovirus-E without imposed symmetry identifies many repeated CP-RNA contacts. These include stem-loops adjacent to the particle two-fold axes, which appear conserved between viruses, as are the amino acid side-chains that contact all the genomic RNA segments. Mutagenesis shows that these amino acids are essential for virion formation, consistent with an RNA-dependent assembly mechanism. These results suggest that all enteroviruses utilise a common assembly mechanism that requires defined CP-RNA contacts.

Rhesus macaque CMV (RhCMV) is an important model for human CMV (HCMV) pathogenesis and vaccine development. Therefore, it is important to understand the similarities and differences in infectivity and interaction of these viruses with their host species. In contrast to the strict species-specificity of HCMV, RhCMV is able to cross species barriers to replicate in human cells. We know from past work that a component of this broader host range is RhCMV’s ability to counteract both the rhesus and human versions of a key antiviral factor. Here we delve further into the mechanisms by which RhCMV can adapt to counteract human cellular defenses. We find that RhCMV appears to be poised to undergo a specific genomic rearrangement that facilitates increased replication efficiency in human cells. Besides providing insights into CMV species-specificity and host barriers to cross-species transmission, this work also provides more generalized clues about viral adaptative mechanisms.

The discovery that the host cell metabolite inositol hexakisphosphate (IP6) stimulates both immature and mature HIV-1 particle assembly began to uncover the mechanism by which HIV-1 particles become infectious. Inhibitors that block HIV-1 capsid assembly effectively lower HIV-1 production in cellulo, however the mechanistic underpinning of how the immature and mature HIV-1 capsids assemble remains enigmatic. We sought to expand upon previous studies and illuminate how IP6, and the related metabolite inositol (1,3,4,5,6) pentakisphosphate (IP5), affect HIV-1 infection. With this goal in mind, we disrupted genes essential for IP5 and/or IP6 production in HIV-1-permissive T cell lines. HIV-1 was less able to propagate in the cells due to defects in intracellular HIV-1 assembly and defects in progeny virion maturation. Our data demonstrate that inositol phosphates are exploited by HIV-1 to orchestrate both virion assembly and maturation. We propose that pharmacological targeting of the HIV-1 inositol phosphate binding pockets in Gag and CA with small molecules will inhibit distinct aspects of HIV-1 replication.

Recombination is an essential part of normal coronavirus replication, required for the generation of the sub-genomic mRNAs as well as defective viral genome (DVGs) and is also implicated in novel strain emergence. However, the molecular mechanisms and determinants of RNA recombination in CoVs are unknown. Here, we compare recombination in 3 divergent beta-coronaviruses; murine hepatitis virus (MHV), MERS-CoV, and SARS-CoV-2. We show that they have striking similarities in the populations of RNA produced and in the sequences surrounding recombination junctions. Further, we demonstrate that the coronavirus proofreading exoribonuclease (nsp14-ExoN) is required to maintain the rates and loci of recombination generated during infection. These data suggest that recombination and the coronavirus exoribonuclease are conserved and important determinants of replication that may be targeted for inhibition and attenuation to control the ongoing pandemic of SARS-CoV-2 and prevent future outbreaks of novel coronaviruses.

Defective viral genomes (DVGs) are produced during virus replication. On their own they cannot replicate, but some of them can compete with wild-type virus for viral and/or cellular resources. For chikungunya virus, interference by DVGs has not been described. Here, we use a new approach based on experimental evolution and computational analysis to characterize all DVGs generated in a virus population and identify those with the highest antiviral potential. We confirm their antiviral activity in both mammalian and mosquito host environments and show that some can broadly interfere with other strains or related alphaviruses. Finally, we show that DVGs can inhibit virus dissemination in mosquitoes.

Lassa virus is the etiological agent of Lassa fever, an haemorrhagic fever endemic that cause nearly 5000 deaths every year in West Africa. Here, we provide the first within-host mathematical model of the infection by Lassa virus in a macaque model and we analyze the antiviral effect of two candidate drugs, favipiravir or ribavirin. We show that both drugs act primarily by increasing mutagenesis in vivo. Both drugs had a strong antiviral efficacy in reducing the proportion of non infectious virus produced by infected cells, up to 91 and 40% for favipiravir and ribavirin, respectively. We bridge these predictions with our knowledge of the drugs pharmacokinetics to identify target concentrations having the capability to rapidly clear infectious virus from infected individuals.

Background

In Zambia, before rotavirus vaccine introduction, the virus accounted for about 10 million episodes of diarrhoea, 63 000 hospitalisations and 15 000 deaths in 2015, making diarrhoea the third leading cause of death after pneumonia and malaria. In Zambia, despite the introduction of the vaccine acute diarrhoea due to rotaviruses has continued to affect children aged five years and below. This study aimed to characterise the rotavirus genotypes which were responsible for diarrhoeal infections in vaccinated infants aged 2 to 12 months and to determine the relationship between rotavirus strains and the severity of diarrhoea in 2016.

Introduction

Combination antiretroviral therapy (cART) improves outcomes for people living with HIV (PLWH) but requires adherence to daily dosing. Suboptimal adherence results in reduced treatment effectiveness, increased costs, and greater risk of resistance and onwards transmission. Treatment with long-acting (LA), injection-based ART administered by healthcare professionals (directly observed therapy (DOT)) eliminates the need for adherence to daily dosing and may improve clinical outcomes. This study reports the cost-effectiveness of the cabotegravir plus rilpivirine LA regimen (CAB+RPV LA) and models the potential impact of LA DOT therapies.

Background

Seasonal influenza is a highly contagious vaccine-preventable disease that may cause high morbidity and mortality in susceptible populations. Healthcare workers are a priority group for seasonal influenza vaccination to protect them from contracting influenza and prevent nosocomial transmission to patients. This study aimed to evaluate knowledge, attitudes, and practices (KAP) of seasonal influenza vaccination among healthcare workers in Honduras.

A curative therapy for HIV-1 infection will at least require the eradication of a small pool of CD4+ helper T cells in which the virus can persist in an inactive, latent state, even after years of successful antiretroviral therapy. It has been assumed that activation of these viral reservoir T cells will also reactivate the latent virus, which is a prerequisite for the destruction of these cells. Remarkably, this is not always the case and following application of even the most potent stimuli that activate normal T cells through their T cell receptor, a large portion of the latent virus pool remains in a dormant state. Herein we demonstrate that a large part of latent HIV-1 infection events reside in T cells that have been rendered activation inert. We provide a systemwide, biomolecular description of the changes that render latently HIV-1 infected T cells activation inert and using this description, devise pharmacologic interference strategies that render initially activation inert T cells responsive to stimulation. This in turn allows for efficient triggering of HIV-1 reactivation in a large part of the otherwise unresponsive latently HIV-1 infected T cell reservoir.

HIV protects its RNA genome while copying it into DNA by carrying out reverse transcription inside its capsid. This is accomplished by importing nucleotides through highly charged pores at the centre of each capsid multimer. These pores contain two rings of positively charged residues–R18 and K25 –but assembling capsids with these features is challenging because they are intrinsically destabilising. Here we show that the metabolite IP6 coordinates both residues within the pore to drive the assembly of stable capsids capable of nucleotide import. R18 or K25 mutants lose infectivity and the ability to synthesise DNA but have differing assembly phenotypes. Mutant K25A is unable to undergo efficient capsid assembly, while replacing K25 with a neutral polar residue partially restores assembly but not infectivity. We propose that IP6-driven assembly is conserved by HIV not because it is the only way to build a capsid, but because it allows the construction of a capsid with a charged pore that can import nucleotides.

Colorectal cancer (CRC) is a leading cause of cancer-related death. The development of CRC can be strongly influenced by specific gut microbes. Understanding how gut microbes modulate CRC is critical to developing novel strategies to improve clinical diagnosis and treatment of this disease. S. gallolyticus subsp. gallolyticus (Sgg) has a strong clinical association with CRC and actively promotes the development of colon tumors. However, the specific Sgg molecules that mediate its pro-tumor activity are unknown. Here we report the first characterization of a type VII secretion system (T7SS) in Sgg, designated as SggT7SS^T05. We further demonstrate that SggT7SS^T05-mediated activities are important for Sgg to colonize the colon and to promote the development of colon tumors. These findings reveal SggT7SS^T05 as a novel pathogenicity determinant of Sgg and provide a critical breakthrough in our efforts to understand how Sgg influences the development of CRC. Future investigations of the biological activities of specific effectors of SggT7SS^T05 will likely lead to the discovery of Sgg molecules that can be used as diagnostic markers and intervention targets aimed at mitigating the harmful effect of Sgg.

The relationship between the infecting dose of a pathogen and the subsequent viral dynamics is unclear in many disease settings, and this relationship has implications for both the timing and the required efficacy of antiviral therapy. Since experimental challenge studies often employ higher doses of virus than would generally be present in natural infection assessment of this relationship is particularly important for translation of findings. In this study we used mathematical modelling of viral load data from a multi-dose study of Zika virus infection in a macaque model to describe the impact of varying the dose of Zika virus on model parameters, and developed a novel mathematical model incorporating viral interference with the innate immune response.

The novel pathogenic coronavirus SARS-CoV-2 causes COVID-19 and remains a threat to global public health. Chloroquine and hydroxychloroquine have been shown to prevent viral infection in cell-culture systems, but human clinical trials did not observe a significant improvement in COVID-19 patients treated with these compounds. Here we show that hydroxychloroquine interferes with only one of two somewhat redundant pathways by which the SARS-CoV-2 spike (S) protein is activated to mediate infection. The first pathway is dependent on the endosomal protease cathepsin L and sensitive to hydroxychloroquine, whereas the second pathway is dependent on TMPRSS2, which is unaffected by this compound. We further show that SARS-CoV-2 is more reliant than SARS coronavirus (SARS-CoV-1) on the TMPRSS2 pathway, and that this difference is due to a furin cleavage site present in the SARS-CoV-2 S protein. Finally, we show that combinations of hydroxychloroquine and a clinically tested TMPRSS2 inhibitor work together to effectively inhibit SARS-CoV-2 entry. Thus TMPRSS2 expression on physiologically relevant SARS-CoV-2 target cells may bypass the antiviral activities of hydroxychloroquine, and explain its lack of in vivo efficacy.

Introduction

Maintaining virologic suppression of children and adolescents on ART in rural communities in sub-Saharan Africa is challenging. We explored switching drug regimens to protease inhibitor (PI) based treatment and reducing nevirapine and zidovudine use in a differentiated community service delivery model in rural Zimbabwe.

Most virus families are composed of large numbers of virus species. However, in general, only a few prototypic viruses are experimentally studied in-depth, and it is often assumed that the obtained results are representative of other viruses in the same family. In order to test this assumption, we compared the sensitivity of the antiviral protein kinase PKR from various mammals to inhibition by multiple orthologs of K3, a PKR inhibitor expressed by several closely related orthopoxviruses. We found strong differences in PKR inhibition by the K3 orthologs, demonstrating that sensitivity to a specific inhibitor was not indicative of broad sensitivity to orthologs of these inhibitors from closely related viruses. We also show that PKR from even closely related species displayed markedly different sensitivities to these poxvirus inhibitors. Furthermore, we identified amino acid residues in these K3 orthologs that are critical for enhanced or decreased PKR inhibition and found that distinct amino acid combinations affected PKRs from various species differently. Our study shows that even closely related inhibitors of an antiviral protein can vary dramatically in their inhibitory potential, and cautions that results from host-virus interaction studies of a prototypic virus genus member cannot necessarily be extrapolated to other viruses in the same genus without experimental verification.

Viral hemorrhagic septicemia virus (VHSV) is a rhabdovirus that causes huge economic losses to the fish culture industry throughout the world. Virulence among naturally occurring VHSV strains varies widely. However, little is known about the viral factors that determine VHSV virulence. Here, we identify a naturally-occurring, single-amino-acid substitution in the VHSV P protein that enhances VHSV virulence in flounder. This amino acid substitution in the P protein was detected only in highly virulent VHSV strains, and it enhances viral RNA synthesis and inhibits the interferon response of host cells early after virus infection. Recombinant VHSV containing this amino acid substitution caused increased mortality in flounder compared with the wild type. This is the first study to identify a naturally occurring amino acid substitution in VHSV that determines its virulence in flounder. We expect that our result can be applied to other fish species, and this finding will provide new opportunities to generate an effective VHSV vaccine.

An adjuvant is the pharmacological agent that is added to vaccines to boost immune responses. Currently, there are only seven FDA-approved adjuvants for human use, and vaccines based on these adjuvants have mainly been evaluated for elicitation of antibody-based immunity. However, vaccines need to also stimulate T cell-mediated immunity to protect against diseases such as AIDS, TB and Malaria. Hence, there is a critical need to develop adjuvants that stimulate protective T cell immunity. Here, we identified an adjuvant (Adjuplex; ADJ) that safely induces strong T cell immunity and protects against virus and intracellular bacteria. We also found that ADJ stimulated T cell immunity by unique mechanisms that did not include metabolic activation of antigen-presenting dendritic cells. Instead, ADJ induced a low metabolic state and engaged mechanisms including lipid pathways and induction of reactive oxygen species to promote activation of T cells by dendritic cells, following vaccination. These data not only provide new mechanistic insights into the mechanisms driving activation of T cells by ADJ, it provides a blue print for what adjuvants need to do to induce protection against infections that require T cell immunity.

The main focus of research into the COVID-19 pandemic is the SARS-CoV-2 Spike (S) protein, which is the viral protein responsible for binding the ACE2 receptor on the host cell. Prior to and after attachment, the S needs to be activated by cellular proteases (e.g. furin, TMPRSS2), triggering the virus entry into the target cell. The unique feature of SARS-CoV-2 S is the presence of a multibasic site, an amino acid motif recognised by furin protease, and whose cleavage activates the S protein. Intensive antiviral research has been focused on developing furin inhibitors against SARS-CoV-2 infection. Here we show that furin is not absolutely required for SARS-CoV-2 virus production, suggesting that current SARS-CoV-2 antiviral therapies based on furin-targeting drugs may not completely prevent viral infection. Apart from the virus entry process, the S protein plays a key role in triggering cell-cell fusion, potentially allowing the quick spread of the virus among neighbouring cells. We show that furin-mediated pre-activation of S protein in virus infected cells is not necessary for triggering cell-cell fusion, while the multibasic site and the concomitant presence of TMPRSS2 protease on host cell membrane plays an important role in orchestrating the formation of multinucleated cells. Our results also suggest a key role of TMPRSS2 protease in promoting S-mediated cell-cell fusion paving the way for utilising a cocktail of inhibitors to efficiently treat SARS-CoV-2 infections.

Background

Visceral leishmaniasis (VL) in HIV-positive individuals is a global health problem. HIV-Leishmania coinfection worsens prognosis and mortality risk, and HIV-Leishmania coinfected individuals are more susceptible to VL relapses. Early initiation of antiretroviral therapy can protect against Leishmania infection in individuals living in VL-endemic areas, and regular use of antiretrovirals might prevent VL relapses in these individuals. We conducted a cross-sectional study in Petrolina, Brazil, an VL-endemic area, to estimate the prevalence of asymptomatic Leishmania cases among HIV-positive outpatients.

Every year up to 90,000 new cases of visceral leishmaniasis (VL) occurs globally. One of the most neglected diseases, VL is endemic in 60 countries in four continents. Brazil is one of seven countries in which 90% of all cases in the world occur. When co-occurring with HIV, VL tends to be more severe than in HIV-negative persons, leading to worse prognosis and frequent relapses. In this study HIV-positive outpatients, aged 18 years or older, under antiretroviral therapy, who were asymptomatic for VL, were tested for Leishmania. We observed a prevalence of 9.11% (44/483) of HIV-Leishmania coinfection. For those HIV-positive/Leishmania-negative individuals who live in VL-endemic areas, early initiation of antiretroviral therapy can be a protective factor against Leishmania infection. On the other hand, for HIV-Leishmania coinfected individuals who regularly use antiretrovirals might prevent VL relapses. Studies centering on asymptomatic Leishmania carriers can be useful for guiding public health measures in VL-endemic areas seeking to control and eliminate the disease.

It is widely known that not all mosquito species serve as medically-important virus’ vectors. Even among the vectors, there are variations in their ability to transmit one virus or the other. Nonetheless, while the known primary vectors’ transmission efficiency is evident, the importance of confirming the ability of other potential vectors is indispensable when it comes to the threat of disease introduction to new areas. Japanese encephalitis is a mosquito-borne disease mainly circulating in Asia. However, pockets of infection have been detected outside this endemic area, where the primary mosquito vector (a Culex species) is almost nonexistent. One possibility is that the causal virus is carried by the invasive mosquito species (an Aedes species), originating from Asia, confirmed to adapt well in Europe and North America. Thus, a thorough evaluation will be needed to determine the competence of both the Culex and Aedes species to transmit Japanese encephalitis virus (JEV). Here, the authors found that although the difference in the transmission efficiency between the Culex and Aedes was significant, their competence as vector is evident. This research provides evidence of the possible relevance of the Aedes species in the distribution and spread of JE into new areas.

Background and aim

A measles outbreak occurred in Greece during 2017–2018 affecting mainly pediatric population. The aim of the study was to describe the epidemiological and clinical characteristics of the cases diagnosed in the major pediatric tertiary hospital of Athens, where 26.5% of national pediatric measles cases were diagnosed and treated.

Analysis of the longest evolutionary experiment with HIV-1 to-date reveals continuous viral adaptation over several years. The authors quantify the environment-specific mutations that arise and determine the fraction of mutations that co-occur with significantly different frequencies than expected by chance.

Background

Until now, no antiviral treatment has been proven to be effective for the coronavirus disease 2019 (COVID-19). The timing of oxygen therapy was considered to have a great influence on the symptomatic relief of hypoxemia and seeking medical intervention, especially in situations with insufficient medical resources, but the evidence on the timing of oxygen therapy is limited.

Until now, no antiviral treatment has been proven to be effective for the coronavirus disease 2019 (COVID-19). The timing of oxygen therapy, which has rarely been mentioned in the current literature, has a great influence on the symptomatic relief of hypoxemia and seeking medical intervention, especially in situations with limited medical resources. It is worthwhile to find clues from the exploratory use of oxygen and antiviral drugs in Wuhan at the beginning of the COVID-29 pandemic. Therefore, in this study, a retrospective review was carried out to identify the risk factors associated with a severe and fatal illness, including the use of antivirus and timing of oxygen therapy. The main differences in the clinical features of patients with different severities of COVID-19 were described and the risk factors were explored to expand the current recommendations for high-risk groups. Initiation of oxygen treatment less than 2 days after onset after onset of hypoxia symptoms and the use of IFN-a among critically ill patients were significantly associated with lower risk of COVID-19 mortality. Our study highlighted the importance of early oxygen therapy and lend support to the potentially beneficial effects of IFNα on critical illness.

HIV-1 strains harboring immune escape mutations can accumulate in circulation, but it remains unclear to what extent these 'escaped' HIV-1 strains continue to evolve under ongoing population-level immune pressures. We investigated population-level changes at HIV-1 Reverse Transcriptase codon 135 (RT135), which is under pressure by T cells restricted by HLA-B*51:01 and B*52:01, highly frequent alleles in Japan. While threonine initially accumulated at RT135, RT135L has subsequently increased markedly. Our findings revealed that RT135V selection by HLA-B*52:01-restricted T-cells led to the creation of a new epitope restricted by HLA-C*12:02, an allele in strong linkage disequilibrium with HLA-B*52:01. HLA-C*12:02-restricted T cells in turn suppressed replication of RT135T virus and selected RT135L. Notably, population-level shifts at this codon are particular to Japan, where HLA-B*52:01-C*12:02 represents the most prevalent HLA haplotype. Our findings highlight multiple virus-specific T cells as dynamic drivers of population-level − and host population-specific − HIV-1 evolution over the long term.

Positive-stranded RNA viruses are major pathogens of plants, humans and animals. These viruses hijack and deform intracellular membranes to build viral replication compartments, which support virus replication. In this paper, the authors have identified the critical roles of cellular membrane-shaping proteins and a unique lipid in the formation of the replicase complex for tomato bushy stunt virus (TBSV). TBSV co-opts and retargets the endosomal sorting nexin-BAR proteins into the large TBSV-induced replication compartment. TBSV also promotes the enrichment of PI(3)P phosphoinositide within the subverted membranes. The interplay between the membrane-shaping proteins, PI(3)P and the viral replication proteins leads to stable membranous structures around the viral replicase, which provide the essential protection of the viral RNAs against the host antiviral responses.

In HIV-1 highly exposed persistently seronegative individuals (HESN), protection is a multifactorial phenomenon whereby mucosal IgA, but not IgG, play a determinant anti-viral role. The HESN IgA response focuses on conserved regions of the HIV-1 envelope gp41 subunit, in contrast with the broader IgG and IgA response observed in HIV-1-infected individuals. How protective only IgA, but not IgG, develop in HESN remains unclear. We addressed the role of the CH1 domain of each isotype in antigen recognition and functions by comparing mucosal gp41 specific Fab-IgA1 (FabA) derived from HESN with paired Fab-IgG1 (FabG). We show that structural differences in the CH1α and γ domains impact affinity constants, FabA having higher affinity for gp41 derived from clade A, B and C. FabA neutralization of clade A, B and C HIV-1 infection and transfer from Langerhans to CD4+T cells were cross clade and higher than that observed with corresponding IgG. Accordingly, FabA and G recognize different gp41 epitopes on gp41 clade A, B and C gp41 crystal structures. Using molecular modeling, we defined a peptide corresponding to one 3-D epitope common to gp41 clade A, B and C gp41 specific for one of the FabA that reverses the FabA neutralizing activities. Altogether, we show here that the CH1 domain influences the antibody paratope and in turn its specificity and functional activities. The FabA cross-clade epitopes retrieved on gp41 could be useful in mucosal vaccine design against HIV-1.

Half the world’s population is at risk of infection from arboviruses transmitted by mosquitoes. Deciphering the viral-host interactions that influence the outcome of arbovirus infection in mosquitoes is beneficial to the development of future vector control strategies to limit arbovirus transmission and viral emergence within the human population. Similar to humans, mosquitoes possess different immune pathways to limit the replication of arboviruses. While the Small Ubiquitin-like MOdifier (SUMO) pathway is known to play an important role in the regulation of immune defences to viral infection in humans, the influence of this pathway during arbovirus infection in mosquito cells is currently unknown. Here we define the conservation, biochemical activity, and tissue distribution of the core effector proteins of the Aedes aegypti SUMOylation pathway. We show that the mosquito SUMOylation pathway plays a broadly antiviral role against a wide range of clinically important arboviruses, including Zika, Semliki Forest, and Bunyamwera viruses. Our findings identify SUMOylation as an important component of the antiviral response to arbovirus infection in mosquito cells.

Mammarenaviruses include emergent pathogens responsible of severe disease in humans in zoonotic events. The ability to use the human Transferrin receptor 1 (hTfR1) strongly correlates with their pathogenicity in humans. We isolated a new infectious Tamiami virus strain (TAMV-FL) from host-seeking ticks, which, contrary to the previous rodent-derived reference strain, can use hTfR1 to enter human cells. Moreover, serial passaging of TAMV-FL in human immunocompetent cells selected for two substitutions in the viral envelope glycoprotein: N151K and D156N. These substitutions increase the ability to highjack hTfR1 and the binding capacity to heparan sulfate proteoglycans and cause delayed endosomal escape. Our findings provide insight into the acquisition of novel traits by currently circulating TAMV that increase its potential to trespass the inter-species barrier.

Viral pathogenesis often is age-dependent, with more severe outcomes for infected fetuses and neonates compared to adults. As neurons age and mature, dendrites and axons polarize with distinct functions that affect neurotropic virus replication and neuronal spread of infection. This study investigates how neuronal maturation of peripheral nervous system neurons, the site of alpha-herpesvirus life-long latency and reactivation, affects replication and neuronal spread of pseudorabies virus. Characterization of infected immature and mature primary cultures of superior cervical ganglionic neurons revealed significant differences in protein composition and cellular processes that affected the activity of Us9, a viral protein required for sorting virus particles into axons. We identified neuronal and viral proteins that interact with Us9 in immature and mature neurons. Among these, we demonstrate that SMPD4/nsMase3, a sphingomyelinase critical for membrane organization and neuronal function, regulates PRV neuronal spread by preventing capsid association with Us9-containing membranes, presenting a possible antiviral function.

Herpes simplex virus type 1 (HSV-1) infects and destroys the outer layer of skin cells, producing lesions known as cold sores. Although these lesions heal, the virus persists in the host for the lifetime and can reactivate to cause new lesions. This is possible because the virus enters the axons of neurones in the skin and moves to their cell bodies located in spinal or cranial nerve bundles called ganglia, where the virus becomes dormant (latent). The most abundant viral RNAs expressed during this state are the latency associated transcripts (LATs), which have been considered a hallmark of HSV-1 latency. Here, we studied HSV-1 infection and spread in human skin. Unexpectedly, we found that the LAT locus is necessary for lesion formation in skin. HSV-1 viruses that were genetically mutated to delete the start of the locus could not spread in skin, whereas viruses with many other genetic mutations had this capacity. Our results suggest that an antiviral drug that inhibits transcripts from this region of the viral genome could block viral spread in skin, or a vaccine could possibly be produced by genetically modifying the virus at the LAT locus and by doing so, limit the virus’ ability become latent in neurones.

Background

Numerous clinical trials and observational studies have investigated various pharmacological agents as potential treatment for Coronavirus Disease 2019 (COVID-19), but the results are heterogeneous and sometimes even contradictory to one another, making it difficult for clinicians to determine which treatments are truly effective.

In this meta-analysis, Min Seo Kim and colleagues synthesise results from randomized trials and observational studies on COVID-19 treatments.

Background

Occult hepatitis B virus (HBV) infection (OBI) is a phase of HBV infection characterised by the presence of HBV DNA in the absence of detectable hepatitis B surface antigen (HBsAg). OBI is of concern in the HIV-infected due to high prevalence and risk of HBV reactivation. The prevalence and clinico-demographic characteristics of OBI in anti-retroviral therapy (ART) naïve HIV infected adults in Kenya is unknown.

Background

Depression is recognized as a prominent health problem and a growing public health concern in HIV-positive youths. Despite this fact, in Ethiopia, there is a dearth of evidence on the prevalence of depression and its associated factors among HIV-positive youths.

New viruses are constantly emerging. The ORFEOME project was based on the hypothesis that every virus, regardless of its molecular makeup and biology should encode functions that intersect the p53 signaling network, since p53 guards the cell from genomic insults, of which depositing a foreign, viral nucleic acid is one. The result of the ORFEOME screen of proteins without any known function, of predicted open reading frames and of suspected non-coding RNAs is the identification of two viral proteins that interact with p53. The first one, orf10, is encoded by Kaposi Sarcoma-associated herpesvirus and the second one, NS2A, is encoded by the Zika virus.

Finding medications or vaccines that may decrease the infectious period of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could potentially reduce transmission in the broader population. We developed a computational model of the U.S. simulating the spread of SARS-CoV-2 and the potential clinical and economic impact of reducing the infectious period duration. Our simulation experiments found that reducing the average infectious period duration could avert a median of 442,852 to 44.4 million SARS-CoV-2 cases, varying the proportion of cases treated, average duration of the infectious period, and the reproductive rate. At $500/person, treating 25% of symptomatic cases saved $209.5 billion (societal perspective, R₀ 2.5). Further reducing the average infectious period duration by 3.5 days averted 7.4 million cases (treating 25% of symptomatic cases). Expanding treatment to 75% of all infected cases, including asymptomatic infections (R₀ 2.5), averted 35.9 million cases and 4 million hospitalizations, saving $48.8 billion (societal perspective and starting treatment after 5% of the population has been exposed). Our study suggests that finding ways to reduce the infectious period of SARS-CoV-2 could help decrease its spread and impact.

Background

Within HIV/HBV infected patients, an increase in HDV infection has been observed; there is inadequate information on HDV prevalence as well as virologic profile in Ghana. This study sought to determine the presence of HDV in HIV/HBV co-infected patients in Ghana.

Antiviral innate immune response is the first line of defence against the invading viruses through type I interferon (IFN) signaling. However, viruses have devised ways to target signaling molecules for aberrant IFN response and worsen the disease outcome. As such, deciphering the roles of new regulators of innate immunity could transform the antiviral treatment paradigm by introducing novel panviral therapeutics designed to reinforce antiviral host responses. This could be of great use in fighting recent outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome MERS-CoV, and the more recent SARS-CoV-2 causing the COVID-19 pandemic. However, aberrant activation of such pathways can lead to detrimental consequences, including autoimmune diseases. Regulation of type I IFN responses is thus of paramount importance. To prevent an uncontrolled response, signaling events happen in discrete subcellular compartments, therefore, distinguishing sites involved in recognition of pathogens and those permitting downstream signaling. Here, we show TFG as a new regulator of type I IFN response allowing the efficient organization of signaling molecules. TFG, thus, further substantiates the importance of the protein trafficking machinery in the regulation of optimal antiviral responses. Our findings have implications for both antiviral immunity and autoimmune diseases.

This study presents an open-source, extensible, multiscale platform for simulating viral immune interactions in epithelial tissues, which enables the rapid development and deployment of sophisticated models of viruses, infection mechanisms and tissue types. The model is used to investigate how potential treatments influence disease progression. Simulation results suggest that drugs which interfere with virus replication (e.g., remdesivir) yield substantially better infection outcomes when administered prophylactically even at very low doses than when used at high doses as treatment for an infection that has already begun.

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cycle threshold (Ct) has been suggested as an approximate measure of initial viral burden. The utility of cycle threshold, at admission, as a predictor of disease severity has not been thoroughly investigated.

Introduction

The potential impact of socio-economic condition on virological suppression during antiretroviral treatment (ART) in sub-Saharan Africa is largely unknown. In this case-control study, we compared socio-economic factors among Ethiopian ART recipients with lack of virological suppression to those with undetectable viral load (VL).

Background

Various factors may determine the duration of viral shedding (the time from infection to viral RNA-negative conversion or recovery) in COVID-19 patients. Understanding the average duration of recovery and its predictors is crucial in formulating preventive measures and optimizing treatment options. Therefore, evidence showing the duration of recovery from COVID-19 in different contexts and settings is necessary for tailoring appropriate treatment and prevention measures. This study aimed to investigate the average duration and the predictors of recovery from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection among COVID-19 patients.

Objectives

To determine rates of annual and durable retention in medical care and viral suppression among patients enrolled in the Peter Ho Clinic, from 2013–2017.

Objective

To explore parents’ and guardians’ views and experiences of accessing National Health Service (NHS) general practices for routine childhood vaccinations during the coronavirus (COVID-19) pandemic in England.

As in adults the general principle that the balance between viral load and immune responses determines disease outcome applies in neonates, although the immune environments and exact mechanisms differ. A better understanding of these differences will improve strategies to optimize protection of the highly susceptible neonatal population. These results also suggest that the environment of the brain may protect T cells from exhaustion.

In spite of the enormous scientific efforts to understand mechanisms of SARS-CoV2-induced disease and to develop strategies to control COVID-19 pandemic, many aspects of SARS-CoV2 biology and pathogenesis remain elusive. Several RNA viruses are able to modulate the host lipid metabolism and to recruit LDs to enhance their replication/particle assembling capacity through mechanisms that vary according to the virus and the host cell infected. The mechanisms and pathways explored by SARS-CoV-2 to support its replication within host cells are still largely unknown. Here we demonstrated that lipid droplets (LDs) participate in SARS-CoV2 infection favoring virus replication and heightening inflammatory mediator production. SARS-CoV2 infection increased the expression of key proteins in the regulation of lipid metabolism and the amounts of LDs per cell. In addition, we have found SARS-CoV2 and/or its components associated with LDs in infected cells, suggestive that LDs are recruited as part of replication compartment. Moreover, pharmacological inhibition of DGAT-1, a key enzyme for LD formation, reduces SARS-CoV2 replication, inflammatory mediator production and cell death. Our findings contribute to unveil the complex mechanism by which SARS-CoV-2 make use of cellular metabolism and organelles to coordinate different steps of the viral replication cycle and host immunity, opening new perspectives for SARS-CoV2 antiviral development.

This study shows that the HIV-1 capsid protein, in addition to its structural role, regulates reverse transcription, an essential metabolic process of the virus, by mediating the import of nucleotides. In addition, host cell metabolites such as inositol phosphates are recruited by the capsid to regulate viral DNA synthesis.

Background

Despite direct-acting antivirals (DAA), aims to “eradicate” viral hepatitis by 2030 remain unlikely. In Nepal, an expert consortium was established to treat HCV through Nepal earthquakes aftermath offering a model for HCV treatment expansion in a resource-poor setting.

Despite very effective antiviral therapies, Hepatitis C virus (HCV) eradication remains a major challenge, especially in resource-limited countries. In Nepal, which ranks among the poorest countries in the world an expert consortium was established to treat HCV patients in six centers throughout the country.

A cohort of 600 individuals with HCV infection and past or current drug use were treated using different treatment strategies over time. Very high treatment response rates were achieved in a difficult-to-treat, low-income population whatever the patient’s profile and disease severity and despite the severe 2015 earthquakes in Nepal. The excellent treatment outcomes observed in this real-life community study should prompt further HCV treatment initiatives in Nepal.

Background

This study attempts to understand coronavirus disease 2019 (COVID-19) vaccine demand and hesitancy by assessing the public’s vaccination intention and willingness-to-pay (WTP). Confidence in COVID-19 vaccines produced in China and preference for domestically-made or foreign-made vaccines was also investigated.

This study investigated vaccine demand and hesitancy by assessing the intention to vaccinate against COVID-19 and willingness-to-pay. We found that a considerable proportion of the public in China has a definite intention to receive the COVID-19 vaccine; a higher proportion expressed a probable intention. Perceived benefits and barriers to vaccination (namely vaccine efficacy and adverse event concerns) of the health belief model constructs were significant predictors of COVID-19 vaccination intent. A substantial proportion was concerned about fake or faulty COVID-19 vaccines; however, this was not a significant predictor of vaccination intention. The willingness-to-pay for the COVID-19 was determined and was found to be positively associated with income. Higher confidence in domestically-made COVID-19 vaccines was also found in this study. The preference for domestically-made over foreign-made COVID-19 vaccines indicates that a future COVID-19 vaccine developed by domestic companies will receive a favourable response from the public in China.The findings of this study provide useful guidance for tailored interventions to enhance the acceptance of a new COVID-19 vaccine once it is available. Promotional messages framing the benefit of vaccination and concerns about new vaccine safety to enhance vaccine uptake is warranted.

The high mutation rate of RNA viruses makes it problematic to understand and resolve the role of recombination in generating genomic variation. Frequent mutations will (1) increase the likelihood of convergent mutations, particularly in regions subject to strong positive selection, causing sequence similarities that can be mistaken for recombination events, and (2) introduce new changes that accumulate and obscure recognition of past recombination events. We analyzed the patterns of recombination across Betacoronaviruses using a dedicated approach to distinguish true recombination from convergent mutations. The Betacoronaviruses comprise several populations that could be considered distinct biological species in that they do not engage in gene flow with one another. Moreover, recombination events within the Sarbecovirus subgenus, which includes SARS-CoV-2, are highly biased and predominate in the spike protein region, implicating recombination as having a substantial role in host tropism and viral ecology.

Zika virus (ZIKV) has emerged worldwide and triggered large outbreaks in human populations. While the yellow fever mosquito Aedes aegypti is considered the primary vector of ZIKV, the Asian tiger mosquito Aedes albopictus has been shown experimentally to transmit the virus and has been involved in a few autochthonous transmission in France in 2019. Here, we provide a comprehensive study on the ability of Ae. albopictus mosquitoes to transmit ZIKV by considering the within-host dynamics of ZIKV infection in humans and its impact on both mosquito infection probability and time to mosquito infectiousness. These empirical data were then leveraged by in silico simulations to embed them into their epidemiological context. Our study reveals a low but existing epidemic potential of Ae. albopictus for ZIKV, whatever their tropical or temperate origins. We identified mosquito density as a predictor for ZIKV outbreak occurrence when vectored by Ae. albopictus. Our findings help to explain the absence of large scale ZIKV epidemics in territories occupied by Ae. albopictus but call for active surveillance and eradication programs to maintain the risk of emergence to a low level.

Viruses can acquire mutations during evolution that alter their virulence. An example of a virus that has shown repeated shifts to higher virulence in response to more efficacious vaccines is the oncogenic Marek’s disease virus (MDV) that infects chickens. Until now, it remained unknown which mutations in the large virus genome are responsible for this increase in virulence. We could demonstrate that very few amino acid changes in the meq oncogene of MDV can significantly alter the virulence of the virus. In addition, these changes also allow the virus to overcome vaccinal protection and enhance the shedding into the environment. Taken together, our data provide fundamental insights into evolutionary changes that allow this deadly veterinary pathogen to evolve towards greater virulence.

This study shows that changing the pattern of N-glycosylation of the pathogenic avian influenza H7N9 virus hemagglutinin protein increases the amount of hemagglutinin incorporated into the viral membrane; the candidate vaccine virus induces neutralizing antibodies and protects animal models from lethal viral challenge.

This study presents the complete historical weekly record of smallpox mortality in London over more than 250 years (1664-1930), describes it using spectral analyses, and discusses it in the context of events and interventions that might have influenced infectious disease dynamics.

Background

Rotavirus vaccine (RV) and pneumococcal vaccine (PCV) decrease diarrheal and respiratory disease incidence and severity, but there are few data about the effects of these vaccines among HIV-exposed uninfected (HEU) children.

Mammalian orthoreoviruses (reoviruses) are nonenveloped viruses that replicate in cytoplasmic membranous organelles called viral inclusions (VIs) where progeny virions are assembled. To better understand cellular routes of nonlytic reovirus exit, we imaged sites of virus egress in infected, nonpolarized human brain microvascular endothelial cells (HBMECs) and observed one or two distinct egress zones per cell at the basal surface. Transmission electron microscopy and 3D electron tomography (ET) of the egress zones revealed clusters of virions within membrane-bound structures, which we term membranous carriers (MCs), approaching and fusing with the plasma membrane. These virion-containing MCs emerged from larger, LAMP-1–positive membranous organelles that are morphologically compatible with lysosomes. We call these structures sorting organelles (SOs). Reovirus infection induces an increase in the number and size of lysosomes and modifies the pH of these organelles from ∼4.5–5 to ∼6.1 after recruitment to VIs and before incorporation of virions. ET of VI–SO–MC interfaces demonstrated that these compartments are connected by membrane-fusion points, through which mature virions are transported. Collectively, our results show that reovirus uses a previously undescribed, membrane-engaged, nonlytic egress mechanism and highlights a potential new target for therapeutic intervention.

Coronaviral genomes code for several proteins, with the large 1a/1ab being expressed directly from genomic (g)RNA. For the expression of other viral proteins, a set of subgenomic mRNAs is produced during replication. It includes mRNAs for structural (S-E-M-N) and accessory proteins. While the function of structural proteins is well described, the function of the latter ones is under debate. Some of them are required for replication, while others are dispensable in vitro but essential in vivo. Initially, 10 open reading frames (ORFs) were annotated in the SARS-CoV-2 genome, amongst which ORF10 is the most peculiar, as it does not share sequence homology with any known protein. Shortly after the genomic sequences became available, speculations on this protein's role in pathogenesis and innate immunity breaching started. Here, we identified two patients infected with SARS-CoV-2 variants with the ORF10 gene prematurely terminated. The disease was not attenuated, and the transmissibility was maintained. The in vitro study showed that the ORF10 is also not essential for replication. Consequently, ORF10 should not be treated as the protein-coding gene, and the genome annotations should be amended.

The RV144 vaccine efficacy trial showed a reduction in HIV-1 infections that associated with binding antibody responses to the Envelope (Env) V1V2 loops but precise mechanisms remain unclear. To evaluate the effect of vaccine priming, we performed a systems serology analysis in 37 vaccine and 63 placebo recipients 6, 12 and 36 months after HIV-1 breakthrough infections. Vaccinees were characterized by strong V1V2-specific antibody responses synergized with V1V2-specific ADCP responses, whereas placebo recipients had stronger IgG3 and gp120-specific responses. The strongest distinguishing feature for vaccinees was IgG4 responses. RV144 vaccination enhanced Fc-mediated effector functions but limited the development of broadly neutralizing antibodies post-infection, which were found in eight placebo recipients but no vaccinee. These data show that RV144 vaccination primed B cells towards specific binding and functional antibody responses, with differences between groups still manifest three years after infection, i.e. on average five years after vaccination. These long-term consequences highlight that imprinting certain functions (while deterring other responses) could offer benefits even for leaky vaccines.

The COVID-19 pandemic has triggered urgent efforts to repurpose available drugs for the treatment of SARS-CoV-2 infection. Synergistic drug combinations are particularly desirable because they allow the achievement of desired efficacies with minimal toxicities. Here, we predict that drugs targeting the host proteases, TMPRSS2 and Cathepsin B/L, which facilitate SARS-CoV-2 entry into cells through independent pathways, would be synergistic. We identified the synergy using a mathematical model and found evidence for it in available in vitro data. We found the estimated usage of the two pathways to vary vastly across cell types, highlighting the need to target both pathways. Our findings would help maximize the impact of combination therapies targeting host proteases involved in SARS-CoV-2 entry, which are currently in clinical trials.