Journal of Virology最新文献

{"title":"Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance.","authors":"Tin Phan, Ruy M Ribeiro, Gregory E Edelstein, Julie Boucau, Rockib Uddin, Caitlin Marino, May Y Liew, Mamadou Barry, Manish C Choudhary, Dessie Tien, Karry Su, Zahra Reynolds, Yijia Li, Shruti Sagar, Tammy D Vyas, Yumeko Kawano, Jeffrey A Sparks, Sarah P Hammond, Zachary Wallace, Jatin M Vyas, Jonathan Z Li, Mark J Siedner, Amy K Barczak, Jacob E Lemieux, Alan S Perelson","doi":"10.1128/jvi.01623-24","DOIUrl":"10.1128/jvi.01623-24","url":null,"abstract":"<p><p>In a subset of SARS-CoV-2-infected individuals treated with the antiviral nirmatrelvir-ritonavir, the virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used a mathematical model to describe the longitudinal viral load dynamics of 51 individuals treated with nirmatrelvir-ritonavir, 20 of whom rebounded. Target cell preservation, either by a robust innate immune response or initiation of N-R near the time of symptom onset, coupled with incomplete viral clearance, appears to be the main factor leading to viral rebound. Moreover, the occurrence of viral rebound is likely influenced by the time of treatment initiation relative to the progression of the infection, with earlier treatments leading to a higher chance of rebound. A comparison with an untreated cohort suggests that early treatments with nirmatrelvir-ritonavir may be associated with a delay in the onset of an adaptive immune response. Nevertheless, our model demonstrates that extending the course of nirmatrelvir-ritonavir treatment to a 10-day regimen may greatly diminish the chance of rebound in people with mild-to-moderate COVID-19 and who are at high risk of progression to severe disease. Altogether, our results suggest that in some individuals, a standard 5-day course of nirmatrelvir-ritonavir starting around the time of symptom onset may not completely eliminate the virus. Thus, after treatment ends, the virus can rebound if an effective adaptive immune response has not fully developed. These findings on the role of target cell preservation and incomplete viral clearance also offer a possible explanation for viral rebounds following other antiviral treatments for SARS-CoV-2.</p><p><strong>Importance: </strong>Nirmatrelvir-ritonavir is an effective treatment for SARS-CoV-2. In a subset of individuals treated with nirmatrelvir-ritonavir, the initial reduction in viral load is followed by viral rebound once treatment is stopped. We show that the timing of treatment initiation with nirmatrelvir-ritonavir may influence the risk of viral rebound. Nirmatrelvir-ritonavir stops viral growth and preserves target cells but may not lead to full clearance of the virus. Thus, once treatment ends, if an effective adaptive immune response has not adequately developed, the remaining virus can lead to rebound. Our results provide insights into the mechanisms of rebound and can help develop better treatment strategies to minimize this possibility.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0162324"},"PeriodicalIF":4.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189671","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":"Enhancing the solubility of SARS-CoV-2 inhibitors to increase future prospects for clinical development.","authors":"Ariel J Kuhn, Victor K Outlaw, Tara C Marcink, Zhen Yu, Megan C Mears, Maria N Cajimat, Dale F Kreitler, Payton R Cleven, Jee Ching Mook, Dennis A Bente, Matteo Porotto, Samuel H Gellman, Anne Moscona","doi":"10.1128/jvi.02159-24","DOIUrl":"https://doi.org/10.1128/jvi.02159-24","url":null,"abstract":"<p><p>SARS-CoV-2 poses an ongoing threat to human health as variants continue to emerge. Several effective vaccines are available, but a diminishing number of Americans receive the updated vaccines (only 22% received the 2023 update). Public hesitancy towards vaccines and common occurrence of \"breakthrough\" infections (i.e.<i>,</i> infections of vaccinated individuals) highlight the need for alternative methods to reduce viral transmission. SARS-CoV-2 enters cells by fusing its envelope with the target cell membrane in a process mediated by the viral spike protein, S. The S protein operates via a Class I fusion mechanism in which fusion between the viral envelope and host cell membrane is mediated by structural rearrangements of the S trimer. We previously reported lipopeptides derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S that potently inhibit fusion by SARS-CoV-2, both <i>in vitro</i> and <i>in vivo</i>. These lipopeptides bear an attached cholesterol unit to anchor them in the membrane. Here, to improve prospects for experimental development and future clinical utility, we employed structure-guided design to incorporate charged residues at specific sites in the peptide to enhance aqueous solubility. This effort resulted in two new, potent lipopeptide inhibitors.</p><p><strong>Importance: </strong>Despite the existence of vaccines for SARS-CoV-2, the constant evolution of new variants and the occurrence of breakthrough infections highlight the need for new and effective antiviral approaches. We have shown that lipopeptides designed to bind a conserved region on the SARS-CoV-2 spike protein can effectively block viral entry into cells and thereby block infection. To support the feasibility of using this approach in humans, we re-designed these lipopeptides to be more soluble, using information about the structure of the spike protein interacting with the peptides to modify the peptide chain. The new peptides are effective against both SARS-CoV-2 and MERS. The lipopeptides described here could serve as treatment for people who are unvaccinated or who experience breakthrough infections, and the approach to increasing solubility can be applied in a broad spectrum approach to treating infections with emerging viruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0215924"},"PeriodicalIF":4.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189660","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":"Targeting Ikaros and Aiolos with pomalidomide fails to reactivate or induce apoptosis of the latent HIV reservoir.","authors":"Rachel D Pascoe, Youry Kim, Ajantha Rhodes, Jesslyn Ong, Carolin Tumpach, Celine Gubser, J Judy Chang, James H McMahon, Sharon R Lewin, Thomas A Rasmussen","doi":"10.1128/jvi.01676-24","DOIUrl":"https://doi.org/10.1128/jvi.01676-24","url":null,"abstract":"<p><p>HIV persists in people living with HIV (PLHIV) on antiretroviral therapy (ART) in long-lived and proliferating latently infected CD4+ T cells that selectively express pro-survival proteins, including the zinc finger proteins, Ikaros and Aiolos. In this study, we investigated whether pomalidomide, an immunomodulatory agent that induces degradation of Ikaros and Aiolos, could increase the death of HIV-infected cells and/or reverse HIV latency. Using an <i>in vitro</i> model of CD4+ T cells infected with a green fluorescent protein (GFP) reporter virus, pomalidomide increased the expression of the pro-survival protein B cell lymphoma (Bcl)-2 and did not increase apoptosis of GFP+ HIV productively infected CD4+ T cells. Pomalidomide also increased the expression of CD155 and UL16-binding protein (ULBP) stress proteins on GFP+ HIV productively infected CD4+ T cells, but this did not translate to enhanced clearance following co-culture with a natural killer (NK) cell line. Using CD4+ T cells from PLHIV on ART, pomalidomide <i>ex vivo</i> activated memory CD4+ T cells resulting in elevated HLA-DR expression and induced CD4+ T cell proliferation but only in the presence of T cell receptor stimulation with anti-CD3 and anti-CD28. There was no effect on cell-associated HIV RNA or the frequency of intact HIV DNA. In conclusion, despite an increase in stress protein expression, promoting Ikaros and Aiolos degradation in CD4+ T cells using pomalidomide did not directly induce apoptosis of HIV-infected cells or induce HIV latency reversal.<b>IMPORTANCE</b>People living with HIV (PLHIV) require lifelong antiretroviral therapy (ART) due to the persistence of latently infected cells. The zinc finger proteins, Ikaros and Aiolos, have recently been implicated in promoting the persistence of latently infected cells. In this study, we investigated the effects of pomalidomide, an immunomodulatory imide drug that induces the degradation of Ikaros and Aiolos, on HIV latency reversal and death of infected cells. Using CD4+ T cells from people living with HIV on suppressive antiretroviral therapy, as well as an <i>in vitro</i> model of productive HIV infection, we found that pomalidomide induced T cell activation and expression of stress proteins but no evidence of latency reversal or selective death of infected cells.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0167624"},"PeriodicalIF":4.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188782","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":"Diversifying T-cell responses: safeguarding against pandemic influenza with mosaic nucleoprotein.","authors":"Hongtae Park, Brock Kingstad-Bakke, Thomas Cleven, Myunghwan Jung, Yoshihiro Kawaoka, M Suresh","doi":"10.1128/jvi.00867-24","DOIUrl":"https://doi.org/10.1128/jvi.00867-24","url":null,"abstract":"<p><p>Pre-existing T-cell responses have been linked to reduced disease severity and better clinical outcomes during the 2009 influenza pandemic and the recent COVID-19 pandemic. We hypothesized that diversifying T-cell responses, particularly targeting conserved viral proteins such as the influenza A virus (IAV) nucleoprotein (NP), could protect against both epidemic and pandemic IAV strains. To test this, we created a mosaic nucleoprotein (MNP) by synthesizing a sequence that maximized the representation of 9-mer epitopes from 7422 NP sequences across human, swine, and avian IAVs. Notably, the MNP sequence showed high homology with the NP of the H5N1 strain affecting dairy cows in the ongoing outbreak. Mucosal immunization with the adjuvanted MNP vaccine induced robust CD8 and CD4 T-cell responses against both known immunodominant and <i>in silico</i> predicted subdominant epitopes. MNP-vaccinated mice challenged with epidemic H1N1 and H3N2 strains, which shared immunodominant CD8 and/or CD4 T-cell epitopes, showed a significant (~4 log) reduction in lung viral load. Importantly, MNP-vaccinated mice challenged with a pandemic H1N1 strain lacking shared immunodominant CD8 or CD4 epitopes exhibited a superior reduction in lung viral load, linked to T-cell responses targeting subdominant epitopes present in both the MNP and pandemic strain NP. These results suggest that a diversified T-cell response induced by the MNP vaccine could provide broad protection against severe disease from both current and emerging IAV strains.</p><p><strong>Importance: </strong>The World Health Organization (WHO) estimates that seasonal influenza causes 3-5 million cases of severe illness annually. The influenza virus frequently undergoes genetic changes through antigenic drift and antigenic shift, resulting in annual epidemics and occasional pandemics. Consequently, a major public health objective is to develop a universal influenza vaccine that offers broad protection against both current and pandemic influenza A strains. In this study, we designed a nucleoprotein (NP) antigen (termed mosaic NP) comprising antigenic regions found in thousands of influenza viruses, aiming to use it as a vaccine to induce broad anti-influenza T-cell responses. Our findings indicate that the mosaic NP vaccine provided significant protection against seasonal H1N1 and H3N2, as well as the pandemic H1N1 strain, demonstrating its effectiveness across various influenza subtypes. These findings suggest that the mosaic NP is a potential universal influenza vaccine antigen, capable of protecting against diverse strains of influenza viruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0086724"},"PeriodicalIF":4.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080624","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":"HSV-1 virions and related particles: biogenesis and implications in the infection.","authors":"Maria Kalamvoki","doi":"10.1128/jvi.01076-24","DOIUrl":"https://doi.org/10.1128/jvi.01076-24","url":null,"abstract":"<p><p>Virion formation and egress are sophisticated processes that rely on the spatial and temporal organization of host cell membranes and the manipulation of host machineries involved in protein sorting, membrane bending, fusion, and fission. These processes result in the formation of infectious virions, defective particles, and various vesicle-like structures. In herpes simplex virus 1 (HSV-1) infections, virions and capsid-less particles, known as light (L)-particles, are formed. HSV-1 infection also stimulates the release of particles that resemble extracellular vesicles (EVs). In productively infected cells, most EVs are generated through the CD63 tetraspanin biogenesis pathway and lack viral components. A smaller subset of EVs, generated through the endosomal sorting complexes required for transport (ESCRT) pathway, contains both viral and host factors. Viral mechanisms tightly regulate EV biogenesis, including the inhibition of autophagy-a process critical for increased production of CD63+ EVs during HSV-1 infection. Mutant viruses that fail to suppress autophagy instead promote microvesicle production from the plasma membrane. Additionally, the viral protein ICP0 (Infected Cell Protein 0) enhances EV biogenesis during HSV-1 infection. The different types of particles can be separated by density gradients due to their distinct biophysical properties. L-particles and ESCRT+ EVs display a pro-viral role, supporting viral replication, whereas CD63+ EVs exhibit antiviral effects. Overall, these studies highlight that HSV-1 infection yields numerous and diverse particles, with their type and composition shaped by the ability of the virus to evade host responses. These particles likely shape the infectious microenvironment and determine disease outcomes.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0107624"},"PeriodicalIF":4.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080631","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":"Chinese sacbrood virus mediates m6A modification to target and suppress the expression of hemolymph maintenance gene AF9, exacerbating bee infections.","authors":"Hua Bai, Yueyu Ma, Huitong Qiu, Yang Qi, Yingshuo Huang, Yaxi Guo, Li Sun, Ming Li, Dongliang Fei, Mingxiao Ma, Yuming Liu","doi":"10.1128/jvi.02117-24","DOIUrl":"https://doi.org/10.1128/jvi.02117-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The Chinese sacbrood virus (CSBV) severely threatens the beekeeping industry, wherein 3- to 5-day-old larvae in the critical differentiation stage are highly susceptible to low levels of CSBV exposure. Once infected, larvae cannot undergo normal pupation, but the pathogenic mechanism remains unclear. Previous studies have shown that m6A modification plays an important regulatory role in larval development during the critical differentiation stage. However, it is unknown whether CSBV infection affects the pupation of honeybee larvae by altering m6A modification. Here, a novel immunoregulatory factor, AF9, was identified in honeybee larvae through combined methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq analysis following CSBV infection. Enzyme-linked immunosorbent assay (ELISA) quantification of m6A methylation in total RNA and MeRIP-qPCR further revealed that CSBV infection of honeybee larvae inhibits the expression of &lt;i&gt;AF9&lt;/i&gt; via m6A modification, thereby hindering the host innate immune response and promoting CSBV replication. MeRIP-qPCR was then used to demonstrate that AcMETTL3 targets and modifies &lt;i&gt;AF9&lt;/i&gt; mRNA, thereby inhibiting &lt;i&gt;AF9&lt;/i&gt; expression. Homology and functional analysis of human-derived &lt;i&gt;AF9&lt;/i&gt; (MLLT3) suggested that AF9 exerted a similar effect as MLLT3 on honeybee hemolymph functioning. dsRNA was then fed to silence genes, followed by RNA extraction and expression analysis from hemolymph. Downregulation of &lt;i&gt;AF9&lt;/i&gt; expression led to decreased numbers of live cells in the hemolymph of honeybee larvae and a reduction in phenoloxidase activity, thereby inhibiting the host immune response. Finally, an &lt;i&gt;Apis mellifera&lt;/i&gt; pupation infection model was constructed to further explore the antiviral activities associated with &lt;i&gt;AmAF9. AmAF9&lt;/i&gt; exerted a similarly significant antiviral effect against deformed wing virus (DWV) and acute bee paralysis virus (ABPV) infections in &lt;i&gt;Apis mellifera&lt;/i&gt; pupae. These results indicate that CSBV infection promotes overall m6A modification in the host and inhibits the expression of &lt;i&gt;AF9&lt;/i&gt; through AcMETTL3 targeting, leading to host immunosuppression and exacerbating honeybee infection. Similarly, &lt;i&gt;AF9&lt;/i&gt; is stably expressed in &lt;i&gt;Apis mellifera&lt;/i&gt; and exhibits the same antiviral effect, making it a broad-spectrum target in honeybee viruses.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;The Chinese sacbrood virus (CSBV) poses a serious threat to the health of &lt;i&gt;Apis cerana&lt;/i&gt; colonies, yet its specific pathogenic mechanism remains unclear. This study shows that infection with CSBV can enhance overall m6A modification levels in &lt;i&gt;Apis cerana&lt;/i&gt; larvae and suppress the expression of &lt;i&gt;AF9&lt;/i&gt; by promoting targeting of AcMETTL3, thereby inhibiting the innate immune response and exacerbating CSBV infection. Further analyses indicated that &lt;i&gt;AF9&lt;/i&gt; functions similarly as the mammalian homologous gene &lt;i&gt;MLLT3&lt;/i&gt; by maintaining normal functions of hemolym","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0211724"},"PeriodicalIF":4.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080623","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":"Novel lineage of anelloviruses with large genomes identified in dolphins.","authors":"Matthew D De Koch, Mart Krupovic, Russell Fielding, Kendal Smith, Kelsie Schiavone, Katharine R Hall, Vincent S Reid, Diallo Boyea, Emma L Smith, Kara Schmidlin, Rafaela S Fontenele, Eugene V Koonin, Darren P Martin, Simona Kraberger, Arvind Varsani","doi":"10.1128/jvi.01370-24","DOIUrl":"10.1128/jvi.01370-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Anellovirus infections are ubiquitous in mammals but lack any clear disease association, suggesting a commensal virus-host relationship. Although anelloviruses have been identified in numerous mammalian hosts, their presence in members of the family Delphinidae has yet to be reported. Here, using a metagenomic approach, we characterize complete anellovirus genomes (&lt;i&gt;n&lt;/i&gt; = 69) from four Delphinidae host species: short-finned pilot whale (&lt;i&gt;Globicephala macrorhynchus&lt;/i&gt;, &lt;i&gt;n&lt;/i&gt; = 19), killer whale (&lt;i&gt;Orcinus orca&lt;/i&gt;, &lt;i&gt;n&lt;/i&gt; = 9), false killer whale (&lt;i&gt;Pseudorca crassidens&lt;/i&gt;, &lt;i&gt;n&lt;/i&gt; = 6), and pantropical spotted dolphin (&lt;i&gt;Steno attenuatus&lt;/i&gt;, &lt;i&gt;n&lt;/i&gt; = 1). Sequence comparison of the open reading frame 1 (ORF1) encoding the capsid protein, the only conserved gene shared by all anelloviruses, shows that the Delphinidae anelloviruses form a novel genus-level clade that encompasses 22 unique species-level groupings. We provide evidence that different Delphinidae species can be co-infected by multiple anelloviruses belonging to distinct species groupings. Notably, the ORF1 protein of the Delphinidae anelloviruses is considerably larger than those encoded by all previously described anelloviruses from other hosts (spanning 14 vertebrate orders and including 27 families). Comprehensive analysis of the ORF1 sequences and predicted protein structures showed that the increased size of these proteins results from divergent elaborations within the capsid-distal P2 subdomain and elongation of the C-terminal domain of ORF1. Comparative structural and phylogenetic analyses suggest that acquisition of the P2 subdomain and its diversification occurred convergently in the anelloviruses associated with primate and Delphinidae hosts. Collectively, our results further the appreciation of diversity and evolution of the ubiquitous and enigmatic viruses in the family &lt;i&gt;Anelloviridae&lt;/i&gt;.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Anelloviruses are ubiquitous in mammals, but their infection has not yet been linked to any disease, suggesting a commensal virus-host relationship. Here, we describe the first anelloviruses associated with diverse species of dolphins. The dolphinid anelloviruses represent a new genus (tentatively named \"Qoptorquevirus\") and encode open reading frame 1 (ORF1) (capsid) proteins that are considerably larger than those encoded by previously described anelloviruses from other hosts. Comprehensive analysis of the ORF1 sequences and predicted protein structures revealed the underlying structural basis for such an extravagant ORF1 size and suggested that ORF1 size increased convergently in the anelloviruses associated with primate and Delphinidae hosts, respectively. Collectively, our results provide insights into the diversity and evolution of &lt;i&gt;Anelloviridae&lt;/i&gt;. Further exploration of the anellovirus diversity, especially in the host species that have not yet been sampled, is expected to further clarify their evolutionary trajecto","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0137024"},"PeriodicalIF":4.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet factor 4-derived C15 peptide broadly inhibits enteroviruses by disrupting viral attachment.","authors":"Shuai Lv, Congyi Li, Zhichao Pei, Ziwei Hu, Yining Du, Baisong Zheng, Wenyan Zhang","doi":"10.1128/jvi.01859-24","DOIUrl":"10.1128/jvi.01859-24","url":null,"abstract":"<p><p>Platelet factor 4 (PF4) has been shown to regulate several viral infections. Our previous study demonstrated that PF4 inhibits the entry of enterovirus A 71 (EV71) and coxsackievirus A16 (CA16), which cause hand, foot, and mouth disease (HFMD). In this study, we report that PF4 also inhibits the circulating HFMD pathogen coxsackievirus A6 (CA6) and the re-emerging enterovirus D68 (EVD68). A 15-amino acid peptide, C15, at the C-terminus of PF4 confers anti-viral activity against multiple enteroviruses (EVs) besides CA6 and EVD68, including EV71 and CA16. Mechanistic studies revealed that wild-type C15 with a net-positive charge (+3), but not its mutants C15M and C15A (both -1), specifically binds to the VP3 capsid protein of CA6 and EVD68, thereby disrupting their attachment to the host cell surface. In addition, VP3 of EVs contains a conserved domain (residues 155-170) crucial for binding to C15. An aspartic acid residue at position 156 imparts a net-negative charge to this domain, which, when substituted with a neutrally charged amino acid, reduces the binding affinity of VP3 for C15. Additionally, C15 protects neonatal mice from lethal challenge upon a CA6 infection. These results suggest that C15 is a promising broad-spectrum anti-viral candidate against multiple EVs.</p><p><strong>Importance: </strong>EVs, which pose a significant public health threat, can be classified into 15 species, with EV-A, -B, -C, and -D infecting humans and causing a wide range of diseases, from mild illnesses, such as HFMD, to more severe conditions, such as acute flaccid paralysis. The emergence of new and alternative strains highlights the urgent need for broad-spectrum anti-viral agents. In this study, we identified that the C15 of PF4 exhibits potent anti-viral activity against multiple EVs by binding to their surface and blocking their entry into host cells. Furthermore, C15 provides significant protection in vivo. These findings highlight the potential of C15 as a broad-spectrum anti-viral candidate. Our study opens a new avenue for developing treatments to combat the diverse and evolving threats posed by EVs.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0185924"},"PeriodicalIF":4.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic analysis of coxsackievirus B3 infection in induced pluripotent stem cell-derived brain-like endothelial cells.","authors":"Sarah F Hathcock, Julia Mamana, Taryn E Keyzer, Nadine Vollmuth, Mohammad-Reza Shokri, Henry D Mauser, Robert N Correll, Daryl W Lam, Brandon J Kim, Jon Sin","doi":"10.1128/jvi.01824-24","DOIUrl":"10.1128/jvi.01824-24","url":null,"abstract":"<p><p>Viral aseptic meningitis is a neuroinflammatory condition that occurs when viruses gain access to the central nervous system (CNS) and induce inflammation. The blood-brain barrier (BBB) is comprised of brain endothelial cells (BECs) that stringently regulate the passage of molecules, toxins, and pathogens from the circulation into the CNS. Through their unique properties, such as complex tight junctions, reduced rates of endocytosis, expression of efflux transporters, and restricted expression of leukocyte adhesion molecules, the BBB is often able to limit pathogen entry into the brain; however, certain neurotropic pathogens, such as coxsackievirus B3 (CVB3) are able to infect the CNS. We have previously demonstrated that CVB3 can infect and disrupt induced pluripotent stem cell-derived brain-like endothelial cells (iBECs), but the host response to this infection remains unknown. Here, we investigate global host transcriptional changes during CVB3 infection of iBECs using RNA sequencing. We validated our data set by exploring pathways altered by CVB3 using quantitative real-time PCR (qPCR) and enzyme-linked immunosorbent assay of upregulated cytokines and interferon signaling molecules.</p><p><strong>Importance: </strong>Coxsackievirus B3 (CVB3) is a leading cause of viral aseptic meningitis that can produce severe disease in susceptible individuals. To gain access to the central nervous system, CVB3 must cross central nervous system barriers, such as the blood-brain barrier. Previously, we have shown that CVB3 infects a human stem cell-derived brain-like endothelial cell model. Here, we report the global transcriptome of stem cell-derived brain-like endothelial cells to CVB3 infection and provide proof-of-concept validation of the dataset using molecular biology techniques. These data could inform novel mechanisms of CVB3-mediated blood-brain barrier dysfunction.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0182424"},"PeriodicalIF":4.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural basis of different neutralization capabilities of monoclonal antibodies against H7N9 virus.","authors":"Bingbing Zhao, Zhenzhao Sun, Shida Wang, Zhibin Shi, Yongping Jiang, Xiurong Wang, Guohua Deng, Peirong Jiao, Hualan Chen, Jingfei Wang","doi":"10.1128/jvi.01400-24","DOIUrl":"10.1128/jvi.01400-24","url":null,"abstract":"<p><p>Neutralizing antibodies (nAbs) are important for the treatment of emerging viral diseases and for effective vaccine development. In this study, we generated and evaluated three nAbs (1H9, 2D7, and C4H4) against H7N9 influenza viruses and found that they differ in their ability to inhibit viral attachment, membrane fusion, and egress. We resolved the cryo-electron microscopy (cryo-EM) structures of H7N9 hemagglutinin (HA) alone and in complex with the nAb antigen-binding fragments (Fabs) and identified the HA head-located epitope for each nAb, thereby revealing the molecular basis and key residues that determine the differences in these nAbs in neutralizing H7N9 viruses. Moreover, we found that the humanized nAb CC4H4 provided complete protection in mice against death caused by a lethal H7N9 virus infection, even when nAb was given 3 days after the mice were infected. These findings provide new insights into the neutralizing mechanism and structural basis for the rational design of H7N9 virus vaccines and therapeutics.IMPORTANCEH7N9 viruses have caused severe infections in both birds and humans since their emergence in early 2013 in China. Their persistent presence and variation in avian populations pose a significant threat to both poultry and humans. There are no treatments for human infections. In this study, we thoroughly investigated the neutralization mechanisms, structural basis, and therapeutic effects of three nAbs (1H9, 2D7, and C4H4) against H7N9 viruses. We revealed the molecular determinants underlying the varied performances of the three nAbs in neutralizing H7N9 viruses and protecting H7N9-infected mice. These insights provide a solid foundation for the rational design of vaccines and therapeutics against H7N9 viruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0140024"},"PeriodicalIF":4.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}