Spotlight
Structure and Assembly
Structure and AssemblyMolecular Basis of Binding between Middle East Respiratory Syndrome Coronavirus and CD26 from Seven Bat SpeciesIn this study, we found that bat CD26s (bCD26s) from different species exhibit large diversities, especially in the region responsible for binding to the receptor binding domain (RBD) of Middle East respiratory syndrome coronavirus (MERS-CoV). However, they maintain the interaction with MERS-RBD at varied affinities and support the entry of pseudotyped MERS-CoV. These bat receptors polymorphisms seem to confer evolutionary pressure for...
Structure and AssemblyBiochemical Reconstitution of HIV-1 Assembly and MaturationAssembly and maturation are essential steps in the replication of orthoretroviruses such as HIV-1 and are proven therapeutic targets. These processes require the coordinated functioning of the viral Gag protein’s multiple biochemical activities. We describe here the development of an experimental system that allows an integrative analysis of how Gag’s multiple functionalities cooperate to generate a retrovirus particle. Our current...
Structure and AssemblyGlycoprotein C of Herpes Simplex Virus 1 Shields Glycoprotein B from Antibody NeutralizationHSV-1 causes lifelong infection in the human population and can be fatal in neonatal and immunocompromised individuals. There is no vaccine or cure, in part due to the ability of HSV to escape the host immune response by various mechanisms. The HSV particle contains at least 15 envelope proteins, four of which are required for entry and replication. This work suggests a novel role for gC in shielding the HSV entry glycoproteins. gC may...
Genome Replication and Regulation of Viral Gene Expression
Genome Replication and Regulation of Viral Gene ExpressionDifferent Degrees of 5'-to-3' DAR Interactions Modulate Zika Virus Genome Cyclization and Host-Specific ReplicationFlaviviruses naturally cycle between the mosquito vector and vertebrate hosts. The disparate hosts provide selective pressures that drive virus genome evolution to maintain efficient replication during host alteration. Host adaptation may occur at different stages of the viral life cycle, since host-specific viral protein processing and virion conformations have been reported in the individual hosts. However, the viral determinants and...
Genome Replication and Regulation of Viral Gene ExpressionThe Ubiquitin-Specific Protease Usp7, a Novel Merkel Cell Polyomavirus Large T-Antigen Interaction Partner, Modulates Viral DNA ReplicationMCPyV is the only human polyomavirus that is associated with cancer; the majority of Merkel cell cancers have a viral etiology. While much emphasis was placed on investigations to understand the transformation process by MCPyV oncoproteins and cellular factors, we have only limited knowledge of cellular factors participating in the MCPyV life cycle. Here, we describe Usp7, a cellular deubiquitination enzyme, as a new factor involved in...
Genome Replication and Regulation of Viral Gene ExpressionRNA Polymerase II Promoter-Proximal Pausing and Release to Elongation Are Key Steps Regulating Herpes Simplex Virus 1 TranscriptionThese data suggest that viral transcription is regulated not only by Pol II recruitment to viral genes but also by control of elongation into viral gene bodies. We provide a detailed map of Pol II occupancy on the HSV-1 genome that clarifies features of the viral transcriptome, including the first identification of Pol II PPP sites. The data indicate that Pol II is recruited to late genes early in infection. Comparing α and β gene...
Genetic Diversity and Evolution
Genetic Diversity and EvolutionEvolutionary Dynamics of Oropouche Virus in South AmericaThe emergence and reemergence of pathogens such as Zika virus, chikungunya virus, and yellow fever virus have drawn attention toward other cocirculating arboviruses in South America. Oropouche virus (OROV) is a poorly studied pathogen responsible for over a dozen outbreaks since the early 1960s and represents a public health burden to countries such as Brazil, Panama, and Peru. OROV is likely underreported since its symptomatology can...
Genetic Diversity and EvolutionImpact of Suboptimal APOBEC3G Neutralization on the Emergence of HIV Drug Resistance in Humanized MiceBoth viral (e.g., RT) and host (e.g., A3G) factors can contribute to HIV sequence diversity. This study shows that suboptimal anti-A3G activity shapes viral fitness and drives viral evolution in the plasma compartment in humanized mice.
Genetic Diversity and Evolution | SpotlightInfluenza B Viruses Exhibit Lower Within-Host Diversity than Influenza A Viruses in Human HostsThe evolution of influenza virus is a significant public health problem and necessitates the annual evaluation of influenza vaccine formulation to keep pace with viral escape from herd immunity. Influenza B virus is a serious health concern for children, in particular, yet remains understudied compared to influenza A virus. Influenza B virus evolves more slowly than influenza A virus, but the factors underlying this are not completely...
Genetic Diversity and EvolutionGenetic Diversity, Compartmentalization, and Age of HIV Proviruses Persisting in CD4+ T Cell Subsets during Long-Term Combination Antiretroviral TherapyThe main barrier to HIV cure is the ability of a genetically diverse pool of proviruses, integrated into the genomes of infected CD4+ T cells, to persist despite long-term suppressive combination antiretroviral therapy (cART). CD4+ T cells, however, constitute a heterogeneous population due to their maturation across a developmental continuum, and the genetic “landscapes” of latent proviruses archived within them...
Virus-Cell Interactions
Virus-Cell InteractionsJC Polyomavirus Infection Reveals Delayed Progression of the Infectious Cycle in Normal Human AstrocytesAnimal models are crucial in advancing biomedical research and defining the pathogenesis of human disease. Unfortunately, not all diseases can be easily modeled in a nonhuman host or such models are cost prohibitive to generate, including models for the human-specific virus JC polyomavirus (JCPyV). JCPyV infects most of the population but can cause a rare, fatal disease, progressive multifocal leukoencephalopathy (PML). There have been...
Virus-Cell InteractionsKaposi’s Sarcoma-Associated Herpesvirus Viral Interleukin-6 Signaling Upregulates Integrin β3 Levels and Is Dependent on STAT3Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of three human malignancies: multicentric Castleman’s disease, primary effusion lymphoma, and Kaposi’s sarcoma. Kaposi’s sarcoma is a highly angiogenic tumor that arises from endothelial cells. It has been previously reported that KSHV infection of endothelial cells leads to an increase of integrin αVβ3, a molecule observed to be involved in the angiogenic process...
Virus-Cell InteractionsEndoplasmic Reticulum (ER) Reorganization and Intracellular Retention of CD58 Are Functionally Independent Properties of the Human Cytomegalovirus ER-Resident Glycoprotein UL148In myriad examples, viral gene products cause striking effects on cells, such as activation of stress responses. It can be challenging to decipher how such effects contribute to the biological roles of the proteins. The HCMV glycoprotein UL148 retains CD58 within the ER, thereby preventing it from reaching the cell surface, where it functions to stimulate cell-mediated antiviral responses. Intriguingly, UL148 also triggers the formation...
Virus-Cell InteractionsPACSIN2 Interacts with Nonstructural Protein 5A and Regulates Hepatitis C Virus AssemblyPACSIN2 is a lipid-binding protein that triggers the tubulation of the phosphatidic acid-containing membranes. The functional involvement of PACSIN2 in the virus life cycle has not yet been demonstrated. We showed that phosphorylation of PACSIN2 displayed a negative effect on NS5A and core interaction. The most significant finding is that NS5A prevents PKCα from binding to PACSIN2. Therefore, the phosphorylation level of PACSIN2 is...
Virus-Cell InteractionsInduction of Kaposi’s Sarcoma-Associated Herpesvirus-Encoded Thymidine Kinase (ORF21) by X-Box Binding Protein 1Spliced X-box binding protein 1 (XBP-1s), part of the unfolded protein response and expressed in developing germinal center B cells, can induce Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic replication and directly activate viral interleukin-6 (vIL-6). We show here that XBP-1s can also directly activate KSHV ORF21, a lytic gene. ORF21 encodes KSHV thymidine kinase (TK), which increases the pool of dTTP for viral replication and...
Virus-Cell InteractionsKaposi's Sarcoma-Associated Herpesvirus LANA Modulates the Stability of the E3 Ubiquitin Ligase RLIME3 ubiquitin ligases mark their substrates for degradation and therefore control the cellular abundance of their substrates. RLIM is an E3 ubiquitin ligase that leads to the ubiquitination and degradation of several transcription regulators, such as LMO2, LMO4, LHX2, LHX3, LDB1, and the telomeric protein TRF1. Here, we show that the Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded LANA protein enhances the ubiquitin ligase...
Virus-Cell Interactions | SpotlightTrypsin Treatment Unlocks Barrier for Zoonotic Bat Coronavirus InfectionOverall, our studies demonstrate that proteolytic cleavage is the primary barrier to infection for a subset of zoonotic coronaviruses. Moving forward, the results argue that both receptor binding and proteolytic cleavage of the spike are critical factors that must be considered for evaluating the emergence potential and risk posed by zoonotic coronaviruses. In addition, the findings also offer a novel means to recover previously...
Virus-Cell Interactions | Spotlightβ-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 ProteinAlthough increasing evidence has demonstrated that HSV-1 subverts host immune responses and establishes lifelong latent infection, the molecular mechanisms by which HSV-1 interrupts antiviral innate immunity, especially the cGAS/STING-mediated cellular DNA-sensing signaling pathway, have not been fully explored. Here, we show that β-catenin promotes cGAS/STING-mediated activation of the IFN pathway, which is important for cellular...
Virus-Cell InteractionsInfluenza Virus Hemagglutinins H2, H5, H6, and H11 Are Not Targets of Pulmonary Surfactant Protein D: N-Glycan Subtypes in Host-Pathogen InteractionsLow-pathogenicity avian influenza virus (LPAIV) subtypes can reassort with circulating human strains and pandemic viruses can emerge in human populations, as was seen in the 1957 pandemic, in which an H2 virus reassorted with the circulating H1N1 to create a novel H2N2 genotype. Lung surfactant protein D (SP-D), a key factor in first-line innate immunity defense, removes influenza type A virus (IAV) through interaction with...
Virus-Cell InteractionsMolecular Mechanism for Antibody-Dependent Enhancement of Coronavirus EntryAntibody-dependent enhancement (ADE) of viral entry has been observed for many viruses. It was shown that antibodies target one serotype of viruses but only subneutralize another, leading to ADE of the latter viruses. Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into...
Virus-Cell InteractionsInvasion of Herpes Simplex Virus 1 into Murine Dermis: Role of Nectin-1 and Herpesvirus Entry Mediator as Cellular Receptors during AgingHSV-1 is a prevalent human pathogen which invades skin and mucocutaneous linings. So far, the underlying mechanisms of how the virus invades tissue, reaches its receptors, and initiates infection are still unresolved. To unravel the mechanical prerequisites that limit or favor viral invasion into tissue, we need to understand the contribution of the receptors that are involved in viral internalization. Here, we investigated the invasion...
Cellular Response to Infection
Cellular Response to InfectionThe IFNL4 Gene Is a Noncanonical Interferon Gene with a Unique but Evolutionarily Conserved RegulationRecent genetic evidence has highlighted how the IFNL4 gene acts in a counterintuitive manner, as patients with a nonfunctional IFNL4 gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation. This suggests that the IFNL4 gene acts in a proviral and anti-inflammatory manner. These surprising but quite clear genetic data have prompted an extensive examination of the basic...
Vaccines and Antiviral Agents
Vaccines and Antiviral AgentsAstrovirus Replication Is Inhibited by Nitazoxanide In Vitro and In VivoHuman astroviruses (HAstV) are thought to cause between 2 and 9% of acute, nonbacterial diarrhea cases in children worldwide. HAstV infection can be especially problematic in immunocompromised people and infants, where the virus has been associated with necrotizing enterocolitis and severe and persistent diarrhea, as well as rare instances of systemic and fatal disease. And yet, no antivirals have been identified to treat astrovirus...
Vaccines and Antiviral AgentsMonoclonal Antibodies with Neutralizing Activity and Fc-Effector Functions against the Machupo Virus GlycoproteinMACV infections are a significant public health concern and lead to high case fatality rates. No specific treatment or vaccine for MACV infections exist. However, cases of Junin virus infection, a related virus, can be treated with convalescent-phase serum. This indicates that a MAb-based therapy for MACV could be effective. Here, we describe several MAbs that neutralize MACV and could be used for this purpose.
Vaccines and Antiviral AgentsTargeting Kaposi's Sarcoma-Associated Herpesvirus ORF21 Tyrosine Kinase and Viral Lytic Reactivation by Tyrosine Kinase Inhibitors Approved for Clinical UseKaposi’s sarcoma-associated herpesvirus (KSHV) is the cause of three human malignancies: Kaposi’s sarcoma, primary effusion lymphoma, and the plasma cell variant of multicentric Castleman disease. Previous research has shown that several cellular tyrosine kinases play crucial roles during several steps in the virus replication cycle.
Pathogenesis and Immunity
Pathogenesis and ImmunityHerpes Simplex Virus 1-Specific CD8+ T Cell Priming and Latent Ganglionic Retention Are Shaped by Viral Epitope Promoter KineticsLatency of HSV-1 in host neurons enables long-term persistence from which reactivation may occur to cause recurrent diseases, such as blinding herpetic stromal keratitis. Latency is not antigenically silent, and viral proteins are sporadically expressed at low levels without full virion production. This protein expression is recognized by ganglion-resident HSV-1-specific CD8+ T cells that maintain a protective resident...
Pathogenesis and ImmunityA MUC16 IgG Binding Activity Selects for a Restricted Subset of IgG Enriched for Certain Simian Immunodeficiency Virus Epitope SpecificitiesUnderstanding how antibodies are distributed in the mucosal environment is valuable for developing a vaccine to block HIV infection. Here, we study an IgG binding activity in MUC16, potentially representing a new IgG effector function that would concentrate certain antibodies within the glycocalyx to trap pathogens before they can reach the underlying columnar epithelial barriers. These studies reveal that rhesus macaque IgG responses...
Pathogenesis and Immunity | SpotlightMutations in the Neuraminidase-Like Protein of Bat Influenza H18N11 Virus Enhance Virus Replication in Mammalian Cells, Mice, and FerretsBats are reservoirs for several severe zoonotic pathogens. The genomes of influenza A viruses of the H17N10 and H18N11 subtypes have been identified in bats, but no live virus has been isolated. The characterization of artificially generated bat influenza H18N11 virus in mammalian cell lines and animal models revealed that this virus can acquire mammal-adapting mutations that may increase its zoonotic potential; however, the wild-type...
Pathogenesis and ImmunityExpression of the Conserved Herpesvirus Protein Kinase (CHPK) of Marek’s Disease Alphaherpesvirus in the Skin Reveals a Mechanistic Importance for CHPK during Interindividual Spread in ChickensMarek’s disease in chickens is caused by Gallid alphaherpesvirus 2, better known as Marek’s disease alphaherpesvirus (MDV). Current vaccines only reduce tumor formation but do not block interindividual spread from chicken to chicken. Understanding MDV interindividual spread provides important information for the development of potential therapies to protect against...
Pathogenesis and ImmunityFunctional Perturbation of Mucosal Group 3 Innate Lymphoid and Natural Killer Cells in Simian-Human Immunodeficiency Virus/Simian Immunodeficiency Virus-Infected Infant Rhesus MacaquesVertical transmission of HIV from mother to child accounts for many of the new cases seen worldwide. There is currently no vaccine to mitigate this transmission, and there has been limited research on the effects that lentiviral infection has on the innate immune system in oral tissues of infected children. To fill this knowledge gap, our laboratory studied infant rhesus macaques to evaluate how acute SIV/SHIV infections impacted ILC3...
Pathogenesis and Immunity | SpotlightChronic Lymphocytic Choriomeningitis Infection Causes Susceptibility to Mousepox and Impairs Natural Killer Cell Maturation and FunctionInfection of adult mice with the clone 13 (CL13) strain of lymphocytic choriomeningitis virus (LCMV) is extensively used as a model of chronic infection. In this paper, we show that mice chronically infected with CL13 succumb to challenge with ectromelia virus (ECTV; the agent of mousepox) and that natural killer (NK) cells in CL13-infected mice are reduced in numbers and have an immature and partially activated phenotype but do respond...
Pathogenesis and Immunity | SpotlightLoss of Resistance to Mousepox during Chronic Lymphocytic Choriomeningitis Virus Infection Is Associated with Impaired T-Cell Responses and Can Be Rescued by ImmunizationChronic viral infections may result in immunosuppression and enhanced susceptibility to infections with other pathogens. For example, we have recently shown that mice chronically infected with lymphocytic choriomeningitis virus (LCMV) clone 13 (CL13) are highly susceptible to mousepox, a disease that is caused by ectromelia virus and that is the mouse homolog of human smallpox. Here we show chronic CL13 infection severely disrupts the...
Pathogenesis and ImmunityLong-Term Protection of Rhesus Macaques from Zika Virus ReinfectionZIKV emerged as a vector-borne pathogen capable of causing illness in infected adults and congenital birth defects in infants born to mothers infected during pregnancy. Despite the decrease in ZIKV cases since the 2015-2016 epidemic, questions concerning the prevalence and longevity of protective immunity have left vulnerable communities fearful that they may become the center of next ZIKV outbreak. Although preexisting herd immunity in...
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Journal of Virology® (JVI) explores the nature of viruses, reporting important new discoveries and pointing to new directions in research.
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