Journal of Virology最新文献

{"title":"Pathological characteristics of a murine oral coxsackievirus A10 infection model.","authors":"Jichen Li, Tianjiao Ji, Qian Yang, Guoyan Zhang, Wei Duan, Rui Wang, Ying Liu, Huijie Li, Qiang Sun, Jianfang Zhou, Yong Zhang","doi":"10.1128/jvi.00937-25","DOIUrl":"https://doi.org/10.1128/jvi.00937-25","url":null,"abstract":"<p><p>Coxsackievirus A10 (CVA10) is an enterovirus that has caused global outbreaks of hand, foot, and mouth disease (HFMD), accompanied by neurological and systemic complications. Animal models that can simulate natural infections are necessary for studying viral pathogenesis. In this study, our objective was to establish a mouse-adapted strain (CVA10-P8) through serial passaging, which was capable of orally infecting 14-day-old ICR mice, leading to hind-limb paralysis and death. Viral titers in various tissues indicated tropism in muscle tissue, with significant increases observed in the brain, lung, and intestinal tissues as the infection progressed. Pathological examination revealed tissue damage in the muscles, brain, lungs, and intestines accompanied by neutrophil infiltration of the brain. Furthermore, flow cytometry and transcriptome analysis revealed metabolic abnormalities, immune system activation, and the promotion of systemic inflammatory responses in the brain, muscle, and lung tissues. In summary, we successfully developed a CVA10 mouse-adapted strain and a corresponding mouse model, providing valuable tools for studying CVA10 pathogenesis and evaluating the efficacy of antiviral interventions.IMPORTANCECVA10 has emerged as a predominant pathogen in the etiology of HFMD, with the potential to elicit neurological manifestations and systemic complications. In this study, we successfully established a novel murine model of CVA10 infection by serially propagating a clinical isolate of CVA10, which enabled oral infection in 14-day-old ICR mice. This model facilitated the investigation of the pathogenesis of CVA10-induced disease. Utilizing this infection model, we employed flow cytometry and transcriptome analysis to elucidate the central nervous system (CNS) inflammatory responses elicited by CVA10 in mice, which closely mimic the natural route of infection. Our findings provide novel insights into the pathophysiological mechanisms underlying CVA10-induced neuroinflammation and pave the way for further research into targeted therapeutic interventions for HFMD associated with CVA10.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0093725"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic resilience or resistance in poultry against avian influenza virus: mirage or reality?","authors":"Paula R Chen, Stephen N White, Lianna R Walker, Darrell R Kapczynski, David L Suarez","doi":"10.1128/jvi.00820-25","DOIUrl":"https://doi.org/10.1128/jvi.00820-25","url":null,"abstract":"<p><p>The unprecedented global spread of the highly pathogenic avian influenza (HPAI) virus in wild birds, poultry, and mammalian species has challenged our control efforts. Alternative approaches to limit avian influenza viruses (AIV) include the development of resilient or resistant chickens. Genetically resilient birds may become infected but can overcome disease, whereas resistant birds prevent virus attachment or entry and do not become infected. The most intensively studied host gene is myxovirus-resistance (<i>Mx</i>), which is expressed via the interferon pathway. Both sensitive and resistant chicken <i>Mx</i> genotypes have been described, but this only provides limited resilience. Acidic nuclear phosphoprotein 32 family member A (<i>ANP32A</i>) has been demonstrated as a host cofactor for AIV replication via interaction with the polymerase. Small nucleotide changes within this gene have demonstrated some promise for the establishment of disease resilience. Certain MHC-defined genetic chicken lines have demonstrated increased resilience with higher innate immune responses, but HPAI-infected birds still have high morbidity and mortality. Alternatively, gene-edited or -transgenic chickens have had some success in increasing resilience. This strategy allows flexibility to include foreign genes, modification of existing genes, or combined approaches to block critical steps in the viral life cycle. Some candidate genes include solute carrier 35A1 (<i>SLC35A1</i>), retinoic acid-inducible gene I (<i>RIG-I</i>), and toll-like receptors 3 and 7 (<i>TLR3/7</i>), but animal testing needs to be conducted. Furthermore, existing hurdles for technology transfer to commercial application from either naturally occurring resistance genes or foreign genes remain high and will require acceptance by both the poultry industry and consumers.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0082025"},"PeriodicalIF":4.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of the changes in substrate specificity of herpes simplex virus 1 protein kinase Us3 on viral infection <i>in vitro</i> and <i>in vivo</i>.","authors":"Saori Shio, Akihisa Kato, Jurika Kawasaki, Kousuke Takeshima, Yuhei Maruzuru, Naoto Koyanagi, Hayato Harima, Yasushi Kawaguchi","doi":"10.1128/jvi.00400-25","DOIUrl":"https://doi.org/10.1128/jvi.00400-25","url":null,"abstract":"<p><p>A serine-threonine protein kinase (PK), Us3, encoded by herpes simplex virus 1 (HSV-1), shares substrate specificity with host cellular PKs, protein kinase A (PKA), and AKT. Many Us3 substrates have been identified, and it is thought that during HSV-1 infection, Us3 fine-tunes the phosphorylation levels of individual substrates within their repertoire. However, the significance of this regulatory fine-tuning by Us3 during HSV-1 infection is poorly understood. Here, we found alanine at position 326 (Ala-326) in Us3 was required for the proper fine-tuning of Us3-mediated phosphorylation across the target repertoire in HSV-1-infected cells. Using recombinant viruses in which Us3 Ala-326 was replaced with valine (A326V) or isoleucine (A326I), we showed these mutations selectively altered the phosphorylation of only a subset of at least 14 Us3 target proteins tested in HSV-1-infected cells, with each mutation generally affecting different targets. Of note, (i) both mutations significantly reduced plaque sizes without affecting viral replication in cell cultures; (ii) the Us3 A326I mutation impaired viral replication in the brains of mice and improved survival following intracranial infection, whereas the Us3 A326V mutation had little effect; and (iii) the Us3 A326V mutation reduced ocular pathogenic manifestations and viral replication in the trigeminal ganglia and brains of mice, thereby improving survival following ocular infection. Taken together, these results suggest that the proper fine-tuning of Us3-mediated phosphorylation across its target repertoire is required for efficient cell-to-cell spread of HSV-1 <i>in vitro</i>, and its replication and pathogenicity <i>in vivo</i>.IMPORTANCEThe activation loop (A-loop) is a conformationally flexible loop that critically regulates cellular protein kinases (PKs), but its role in viral PKs during infection remains unclear. We demonstrated alanine at position 326 (Ala-326) in the A-loop of herpes simplex virus 1 (HSV-1) PK Us3 was important for the proper fine-tuning of Us3-mediated phosphorylation across the target repertoire in HSV-1-infected cells. This fine-tuning was necessary for efficient HSV-1 cell-cell spread in cell cultures, and replication and pathogenicity in mice. Taken together, fine-tuning phosphorylation levels of individual Us3 targets within its repertoire is important for HSV-1 infection <i>in vitro</i> and <i>in vivo</i>. Different amino acid substitutions at Us3 Ala-326 selectively affected the phosphorylation of most distinct Us3 targets, leading to varied phenotypic outcomes in viral replication and pathogenicity in mice. These results provide important clues to elucidate the mechanisms by which Us3 regulates HSV-1 infection <i>in vivo</i>.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0040025"},"PeriodicalIF":4.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Syndecan 2 proteoglycan serves as a hepatitis B virus cell attachment receptor.","authors":"Sachin Kumar Tripathi, Yingying Li, Guangxiang Luo","doi":"10.1128/jvi.00796-25","DOIUrl":"https://doi.org/10.1128/jvi.00796-25","url":null,"abstract":"<p><p>We have previously found that human apolipoprotein E (apoE) is enriched on the envelope of infectious hepatitis B virus (HBV) and plays an important role in HBV infection and morphogenesis. Recently, we have demonstrated that the low-density lipoprotein receptor (LDLR) is required for efficient HBV infection. LDLR is a known apoE-binding receptor. Additionally, heparan sulfate proteoglycans (HSPGs) serve as apoE-binding receptors. HSPGs are implicated in HBV infection as HBV cell attachment receptors. HSPGs are composed of heparan sulfate glycosaminoglycans covalently attached to core proteins, including syndecans (SDC1-SDC4) and glypicans (GPC1-GPC6). GPC5 was previously reported as an HBV entry-promoting factor. In the present study, we have identified SDC2 as another cell attachment receptor promoting HBV infection. Small interfering RNA (siRNA)-induced silencing of SDC2 expression resulted in a significant reduction of HBV infection. Likewise, SDC2 gene knockout decreased the susceptibility of hepatocytes to HBV infection. However, the defective HBV infection in the SDC2-deficient hepatocytes could be fully restored by ectopic SDC2 expression. The importance of SDC2 in HBV infection was validated using primary human hepatocytes. Moreover, SDC2 deficiency lowered preS1- and apoE-binding and consequently HBV attachment to the surface of hepatocytes. Collectively, our findings suggest that SDC2 functions as an HBV cell attachment receptor.IMPORTANCEMany different DNA and RNA viruses use HSPGs as cell attachment receptors. HSPGs are composed of core proteins and covalently attached heparan sulfate glycosaminoglycans. Individual SDCs and GPCs play distinct roles in the mediation of cell attachment of different viruses. GPC5 was previously found to promote HBV infection. However, the role of SDCs in HBV infection has not been experimentally examined. In the present study, we have identified SDC2 as an HBV cell attachment receptor. We further found that SDC2-deficient hepatocytes are much less susceptible to preS1- and apoE-binding. These findings suggest that SDC2 promote HBV infection likely through interactions with apoE and preS1, both of which are present on the surface of HBV envelope and contain HSPG-binding sites.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0079625"},"PeriodicalIF":4.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rabies virus utilizes neuropilin 2 as an endocytic receptor to trigger TGFBR1-mediated actin polymerization.","authors":"Ziruo Sun, Jinqiu Wang, Zhiyuan Wen, Lei Shuai, Wenjing Sun, Mengjie Yang, Jinyu Wang, Junyu Chen, Jinying Ge, Weiye Chen, Xijun Wang, Zhigao Bu, Jinliang Wang","doi":"10.1128/jvi.00638-25","DOIUrl":"https://doi.org/10.1128/jvi.00638-25","url":null,"abstract":"<p><p>Rabies virus (RABV), belonging to the rhabdovirus, is a typical large virus that enters cells via clathrin-mediated endocytosis (CME). RABV-containing pits are only partially clathrin-coated and require local actin polymerization for efficient internalization. This unconventional entry process suggests that a specific receptor may be required to initiate actin polymerization during RABV entry. Here, we found that RABV uses the cell membrane protein neuropilin 2 (NRP2) to initiate F-actin polymerization. NRP2 is required for RABV infection and directly interacts with RABV glycoprotein. An antibody against the ectodomain of NRP2 and the soluble ectodomain of NRP2 blocked RABV infection in cells. Expression of human NRP2 in non-susceptible DU145 cells enabled RABV infection. We further found that NRP2 interacted with transforming growth factor-β receptor I (TGFBR1), triggering TGFBR1/2-Cdc42-mediated F-actin polymerization. Vesicular stomatitis virus, another prototypical rhabdovirus, also uses a similar mechanism to enter cells. Our findings demonstrate that NRP2 is a novel receptor for RABV entry by transducing the signal of viral binding across the plasma membrane to initiate actin polymerization. NRP2 may represent one of the long-sought molecules that facilitate large pathogen cell entry via CME.IMPORTANCERabies virus (RABV) enters cells via clathrin-mediated endocytosis (CME), but RABV-containing pits are only partially clathrin-coated, requiring actin polymerization for efficient entry. However, how the virus triggers the actin polymerization remains unclear. Here, we found that the cell membrane protein neuropilin 2 (NRP2) is required for RABV infection and directly interacts with RABV glycoprotein. An antibody against the ectodomain of NRP2 and the soluble ectodomain of NRP2 blocked RABV infection in cells. Expression of human NRP2 in non-susceptible DU145 cells enabled RABV infection. We further found that NRP2 interacted with transforming growth factor-β receptor I (TGFBR1), triggering TGFBR1/2-Cdc42-mediated F-actin polymerization. Vesicular stomatitis virus, another prototypical rhabdovirus, also uses a similar mechanism to enter cells. Our findings demonstrate that NRP2 is a novel receptor for RABV entry by initiating actin polymerization and may represent one of the long-sought molecules that facilitate large pathogen cell entry via CME.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0063825"},"PeriodicalIF":4.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental and evolutionary evidence for horizontal transfer of an envelope fusion protein gene between thogotoviruses and baculoviruses.","authors":"Bruno Milhomem Pilati Rodrigues, Luis Janssen, Leonardo Assis da Silva, Suzane Suliane Vitorino Gomes Acacio, Mariana Tigano Magalhães, Bergmann Morais Ribeiro","doi":"10.1128/jvi.02148-24","DOIUrl":"https://doi.org/10.1128/jvi.02148-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Baculoviruses are insect-specific viruses with large, double-stranded DNA genomes classified into four genera. Alphabaculoviruses, which infect lepidoptera, are further divided into group I (G1-α) and group II (G2-α). The GP64 protein, essential for cell attachment and viral entry in G1-α baculoviruses, is thought to have originated through horizontal gene transfer (HGT) from thogotoviruses (family &lt;i&gt;Orthomyxoviridae&lt;/i&gt;). This study investigates the functional substitution of GP64 by thogotovirus fusion proteins. Through RNA-seq data mining, we identified a novel thogotovirus, Melitaea didyma thogotovirus 1 (MediTHOV-1), in lepidopteran hosts. Phylodynamic analysis of G1-α baculovirus and thogotovirus glycoproteins suggests that the HGT event occurred during the Mesozoic era. To test functional substitution, we constructed recombinant Autographa californica multiple nucleopolyhedrovirus (AcMNPV) carrying either the envelope fusion protein (EFP) genes from MediTHOV-1 or Apis thogotovirus 1 (ATHOV-1), while deleted for its native &lt;i&gt;gp64&lt;/i&gt; gene. Our results show that, while the MediTHOV-1 glycoprotein failed to rescue AcMNPV infectivity, the ATHOV-1 fusion protein (EFP) partially restored infectivity, albeit with reduced efficiency. Cryo-electron microscopy revealed lower incorporation of ATHOV-1 EFP into viral envelopes compared to GP64. The recombinant AcMNPV carrying ATHOV-1 EFP (Ac-ATHOVGPgp64Δ) displayed delayed replication kinetics and lower viral titers. Interestingly, ATHOV-1 EFP significantly enhanced baculovirus entry and gene transduction in mosquito cells. These findings provide experimental support for the HGT hypothesis, demonstrating the functional incorporation of a thogotovirus glycoprotein into a baculovirus. This study sheds light on the evolutionary relationship between baculovirus GP64 and glycoproteins, offering insights into viral evolution and potential biotechnological applications in gene delivery and protein expression.IMPORTANCEBaculoviruses are widely utilized for the biological control of insect pests and as versatile biotechnological tools, with their effectiveness largely dependent on the activity of their envelope fusion proteins (EFPs). Thogotoviruses, in contrast, are emerging vector-borne pathogens of significant concern. In this study, we present the first successful functional substitution of the baculovirus GP64 protein with a thogotovirus EFP, alongside the identification of what appears to be a lepidopteran-associated thogotovirus, Melitaea didyma thogothovirus 1. Our work provides functional and phylogenetic insights into the evolutionary relationship between these distantly related viral groups, particularly the hypothesized horizontal gene transfer event that gave rise to baculoviral &lt;i&gt;gp64&lt;/i&gt; gene. These findings offer a deeper understanding of the determinants underlying the adaptation of baculoviral glycoproteins to novel hosts. Furthermore, the discovery of novel viral genes highlights pro","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0214824"},"PeriodicalIF":4.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CypA inhibits respiratory syncytial virus (RSV) replication by suppressing glycolysis through the downregulation of PKM2 expression.","authors":"Jing Zhang, Miao Li, Jing Cheng, Yutong Wang, Cuiqing Ma, Lizheng Yin, Jiachao Wang, Xue Gao, Wenzhang Liang, Lin Wei","doi":"10.1128/jvi.00074-25","DOIUrl":"https://doi.org/10.1128/jvi.00074-25","url":null,"abstract":"<p><p>The \"Warburg effect,\" a type of metabolic reprogramming characterized by enhanced glycolysis even in the presence of oxygen, is frequently observed in tumor cells and has also been detected in cells infected with viruses. Our study demonstrated that respiratory syncytial virus (RSV) infection induced aerobic glycolysis both <i>in vivo</i> and <i>in vitro</i>. By utilizing the glycolysis agonist PS48 or inhibitor 2-DG, we ascertained that RSV can utilize glycolysis to promote its replication. Mechanistically, glycolysis may facilitate RSV replication by negatively regulating the IFNβ response. Additionally, we discovered a host molecule, namely CypA, that could downregulate glycolysis to combat RSV infection. CypA interacted with PKM2, a key enzyme of glycolysis, and reduced its expression. By overexpressing or knocking down CypA, we verified that CypA could inhibit aerobic glycolysis, enhance IFNβ production, and reduce RSV replication. Inhibiting the PPIase activity of CypA resulted in the disappearance of its function, indicating that CypA exerted its effects dependent on PPIase activity. Furthermore, we found that CypA has a synergistic effect with 2-DG and an antagonistic effect with PS48 on the IFNβ response, supporting the notion that CypA regulates IFNβ by inhibiting glycolysis. These results indicate that CypA may serve as a novel host factor in the regulation of glycolysis, the interferon response, and ultimately in resisting RSV infection.</p><p><strong>Importance: </strong>Viruses utilize the host's resources and energy to carry out essential life processes and achieve self-replication. In response, hosts have evolved a range of antagonistic mechanisms. Our study investigates how RSV employs glycolysis to benefit its replication, with a particular focus on the interaction between glycolysis and IFNβ regulation. Additionally, we explore how the host employs CypA to antagonize the virus's utilization of glycolysis, thereby inhibiting RSV replication. Our findings will contribute to the development of effective antiviral therapies targeting CypA.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0007425"},"PeriodicalIF":4.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD317 functions as a key antiviral factor in human herpesvirus 6 (HHV-6) infection.","authors":"Xianyi Xu, Minmin Song, Xin Zhang, Junli Jia, Shuhua Chen, Hua Xie, Lingyun Li, Jingjing Ma, Huamin Tang","doi":"10.1128/jvi.00841-25","DOIUrl":"https://doi.org/10.1128/jvi.00841-25","url":null,"abstract":"<p><p>CD317, an interferon-stimulated gene, is known for its role in inhibiting the release of various enveloped viruses from infected cells. However, its function can vary, as it also promotes infection in certain contexts, such as with human cytomegalovirus (HCMV). Human herpesvirus 6 (HHV-6) and HCMV are both classified within the β-herpesvirus subfamily. The role of CD317 in HHV-6 infection has not been previously investigated. In this study, we found that (i) HHV-6 infection induces CD317 expression, which in turn restricts HHV-6 infection, (ii) type I interferon stimulation induces CD317 expression, thereby inhibiting HHV-6 infection, (iii) the HHV-6 envelope glycoprotein O (gO) interacts with CD317, leading to gO degradation, and (iv) CD317 is incorporated into HHV-6 virions. This work represents the first report elucidating the role of CD317 in HHV-6 infection and reveals a novel function of gO in this process.</p><p><strong>Importance: </strong>Upon stimulation with type I interferon, hundreds of interferon-stimulated genes (ISGs) are induced to express. For an individual virus, it is crucial to identify and analyze the key ISGs. Here, we discovered that CD317 is one of the key ISGs that restrict HHV-6 infection. While CD317 is well known for its ability to inhibit the release of progeny virions, we have revealed a novel role for CD317 in restricting HHV-6 infection by inhibiting viral entry. Additionally, we found that CD317 interacts with HHV-6 glycoprotein O (gO), a protein of unknown function, leading to the proteasomal degradation of gO. This finding may provide valuable clues for further analysis of gO's function.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0084125"},"PeriodicalIF":4.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enterovirus C recombination groups: RNA sequence similarity and the viral polymerase underpin sexual replication mechanisms.","authors":"Evan M Okolovitch, Vishnu Govindarajan, Refugio Robles-Sikisaka, Grace Campagnola, Brian J Kempf, Andrew L Routh, Olve B Peersen, David J Barton","doi":"10.1128/jvi.00434-25","DOIUrl":"https://doi.org/10.1128/jvi.00434-25","url":null,"abstract":"<p><p>Enteroviruses frequently recombine with one another in nature; however, it is unclear how viral replication machinery can distinguish between related and unrelated partners during recombination. We hypothesize that viral RNA recombination involves two parental RNA templates, nascent RNA products, and their dynamic interactions with the viral polymerase-a sexual replication strategy. When nascent RNA products move from one parental RNA template to another, RNA sequence similarity may be an important factor underpinning the mechanism and efficiency of recombination. To test this hypothesis, we focused on recombination between two related group C enteroviruses, poliovirus and Coxsackievirus A21 (CVA21), using bioinformatic, biological, and biochemical approaches. Bioinformatic analyses comparing 22 prototypical group C enteroviruses delineated four recombination groups where viruses in each group exhibit high RNA sequence and amino acid similarity in their polymerase genes. ClickSeq and ViReMa methods detect recombinant forms of poliovirus with P3 genes from CVA21, analogous to recombinant circulating vaccine-derived polioviruses (cVDPV). Biochemical assays show that poliovirus and CVA21 polymerases can detect mismatched base pairs as they traverse an extended primer grip surface adjacent to the active site. Mismatched base pairs in the -2 and -3 positions destabilize polymerase elongation complexes, consistent with the predicted role of RNA sequence similarity in recombination. Two subgroup-specific genetic elements, upstream open-reading frames (uORFs) and RNase L competitive inhibitor RNAs (RNase L ciRNAs), reinforce the existence and biological relevance of enterovirus C recombination groups. Altogether, our observations suggest that enterovirus RNA replication machinery can distinguish between related and unrelated partners during recombination.</p><p><strong>Importance: </strong>Viral RNA recombination transforms live-attenuated polioviruses into neurovirulent circulating vaccine-derived polioviruses, complicating the planned eradication of poliovirus. When humans are co-infected with poliovirus and related non-polio enteroviruses, viral replication machinery can produce recombinant viruses. However, who recombines with whom? What factors determine whether two distinct viruses can produce recombinant progeny that are fit for transmission from person to person? In this study, we clarify which viruses recombine with one another in nature and further elucidate the mechanisms by which the viral polymerase distinguishes between related and unrelated RNA templates-a sexual form of replication. Understanding these mechanisms could lead to better strategies for virus control and/or eradication.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0043425"},"PeriodicalIF":4.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of Nef in the long-term persistence of the replication-competent HIV reservoir in South African women.","authors":"Sherazaan D Ismail, Shorok Sebaa, Bianca Abrahams, Martha C Nason, Mitchell J Mumby, Jimmy D Dikeakos, Sarah B Joseph, Matthew Moeser, Ronald Swanstrom, Nigel Garrett, Carolyn Williamson, Thomas C Quinn, Melissa-Rose Abrahams, Andrew D Redd","doi":"10.1128/jvi.00217-25","DOIUrl":"10.1128/jvi.00217-25","url":null,"abstract":"<p><p>HIV-1 Nef mediates immune evasion and viral pathogenesis in part through the downregulation of cell surface cluster of differentiation 4 (CD4) and major histocompatibility complex class I (MHC-I) on infected cells. While the Nef function of circulating viral populations found early in infection has been associated with reservoir size in early-treated cohorts, there is limited research on how its activity impacts reservoir size in people initiating treatment during chronic infection. In addition, there is little research on its role in the persistence of viral variants during long-term antiretroviral therapy (ART). Phylogenetically distinct <i>nef</i> genes (<i>n</i> = 82) with varying estimated times of reservoir entry were selected from viral outgrowth variants stimulated from the reservoir of South African women living with HIV who initiated ART during chronic infection (<i>n</i> = 16). These <i>nef</i> genes were synthesized and used in a pseudovirus infection assay that measures CD4 and MHC-I downregulation via flow cytometry. Downregulation measures were compared to the size of the replication-competent viral reservoir (RC-VR), estimated by quantitative viral outgrowth assay at 5 years after treatment initiation, as well as proviral survival time. Maximum Nef-mediated MHC-I downregulation was significantly associated with RC-VR size (<i>P</i> = 0.034), but this association was not observed for CD4 downregulation. Conversely, we did not find a consistent association between intraparticipant MHC-I or CD4 downregulation and the variant timing of entry into the reservoir. These data support a role for Nef-mediated MHC-I downregulation in determining RC-VR size, but more work is needed to determine Nef's role in the survival of individual viral variants over time.IMPORTANCERational design of HIV cure interventions requires an understanding of the viral determinants of reservoir dynamics. For an equitable cure, it needs to be broadly applicable. While African women bear the greatest burden of HIV globally, most cure research has focused on men in the global North. Our study aims to elucidate viral determinants of HIV persistence in South African women on antiretroviral therapy. We hypothesized that the HIV protein Nef subverts immune clearance of infected cells by downregulating surface levels of two cellular proteins, CD4 and MHC-I. We compared this downregulation capacity with reservoir size and variant survival in the reservoir. We found a positive association between an individual's reservoir size and MHC-I downregulation, but there was little evidence for a survival benefit with stronger MHC-I reduction. These data support earlier work and suggest that Nef's interaction with MHC-I may be a target to restrict the latent reservoir in cure strategies.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0021725"},"PeriodicalIF":4.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}