Journal of Virology最新文献

{"title":"HSV-1 virions and related particles: biogenesis and implications in the infection.","authors":"Maria Kalamvoki","doi":"10.1128/jvi.01076-24","DOIUrl":"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":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915793/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A conserved lysine/arginine-rich motif is essential for the autophagic degradation of potyviral 6K1 protein and virus infection.","authors":"Weiyao Hu, Changhui Deng, Li Qin, Peilan Liu, Linxi Wang, Xaioqing Wang, Wei Shi, Asma Aziz, Fangfang Li, Xiaofei Cheng, Aiming Wang, Zhaoji Dai, Xiaohua Xiang, Hongguang Cui","doi":"10.1128/jvi.02183-24","DOIUrl":"10.1128/jvi.02183-24","url":null,"abstract":"<p><p>Potyviruses possess one positive-sense single-stranded RNA genome, mainly dependent on polyprotein processing as the expression strategy. The resulting polyproteins are proteolytically processed by three virus-encoded proteases into 11 or 12 mature proteins. One such factor, 6 kDa peptide 1 (6K1), is an understudied viral factor. Its function in viral infection remains largely mysterious. This study is to reveal part of its roles by using pepper veinal mottle virus (PVMV) as the model. Alanine substitution screening analysis revealed that 15 of 17 conserved residues across potyviral 6K1 sequences are essential for PVMV infection. However, 6K1 protein is less accumulated in virus-infected cells, although P3-6K1 and 6K1-CI junctions are efficiently processed by NIa-Pro for its release, indicating that 6K1 undergoes a self-degradation event. Mutating the cleavage site to prevent NIa-Pro processing abolishes viral infection, suggesting that the generation of 6K1 along with its degradation might be important for viral multiplication. We corroborated that cellular autophagy is engaged in 6K1's degradation. Individual engineering of the 15 6K1 variants into PVMV allows their expression along with viral infection. Five of such variants, D30A, V32A, K34A, L36A, and L39A, significantly interfere with viral infection. The five residues are enclosed in a conserved lysine/arginine-rich motif; four of them appear crucial in engaging autophagy-mediated self-degradation. Based on these data, we envisaged a scenario which potyviral 6K1s interact with an unknown anti-viral component to be co-degraded by autophagy to promote viral infection.IMPORTANCE<i>Potyvirus</i> is the largest genus of plant-infecting RNA viruses, which encompasses socio-economically important virus species, such as <i>Potato virus Y</i>, <i>Plum pox virus</i>, and <i>Soybean mosaic virus</i>. Like all picorna-like viruses, potyviruses express their factors mainly via polyprotein processing. Theoretically, viral factors P3 through CP, including 6K1, should share an equivalent number of molecules. The 6K1 is small in size (~6 kDa) and conserved across potyviruses but less accumulated in virus-infected cells. This study demonstrates that cellular autophagy is engaged in the degradation of 6K1 to promote viral infection. In particular, we found a conserved lysine/arginine-rich motif in 6K1s across potyviruses that is engaged in this degradation event. This finding reveals one facet of a small protein that helps understand the pro-viral role of cellular autophagy in viral infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0218324"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382745","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":"Deglycosylation and truncation in the neuraminidase stalk are functionally equivalent in enhancing the pathogenicity of a high pathogenicity avian influenza virus in chickens.","authors":"Daiki Kobayashi, Takahiro Hiono, Hiromu Arakawa, Hiroyuki Kaji, Ayako Ohkawara, Takaya Ichikawa, Hinako Ban, Norikazu Isoda, Yoshihiro Sakoda","doi":"10.1128/jvi.01478-24","DOIUrl":"10.1128/jvi.01478-24","url":null,"abstract":"<p><p>Influenza A viruses with fewer amino acids in the neuraminidase (NA) stalk domain are primarily isolated from chickens rather than wild ducks, indicating that a shortened NA stalk is considered an adaptation marker of avian influenza viruses (AIVs) to chickens. Experimental passages of an H7N7 nonpathogenic AIV (rgVac2-P0) in chickens resulted in a highly pathogenic variant (Vac2-P3L4) with a 34-amino-acid deletion in the NA stalk, encompassing five potential <i>N</i>-glycosylation sites. To investigate how amino acid truncation and deglycosylation in the NA stalk contribute to increased pathogenicity, a virus with glycosylation-deficient mutations at these sites (rgVac2-P3L4/P0NAΔGlyco) was constructed. Contrary to expectations, chickens inoculated with rgVac2-P3L4/P0NAΔGlyco exhibited variable clinical outcomes, attributed to the genetic instability of the virus. A single mutation stabilized the virus, and the mutant (rgVac2-P3L4/P0NAΔGlyco-Y65H) resulted in higher pathogenicity compared with a virus with restored glycosylation (rgVac2-P3L4/P0NA-Y65H). Glycan occupancy analysis revealed 3-4 glycans at the five potential sites. In functional analysis, glycosylation-deficient mutants, similar to the short-stalk NA virus, showed significantly reduced erythrocyte elution activity. Additionally, mutational analysis indicated variable contributions of <i>N</i>-glycans to elution activity across the sites. Moreover, the functionally most contributing sites of the five potential <i>N</i>-glycosylation motifs were consistently included in the amino acid deletions of the stalk-truncated NA in N7-subtyped field isolates, despite the varying truncation position or length. These findings suggest that the loss of glycosylation is functionally equivalent to a reduction in amino acids, and it plays a crucial role in enhancing pathogenicity in chickens and affecting NA function.IMPORTANCEAvian influenza poses significant economic challenges to the poultry industry and presents potential risks to human health. Understanding the molecular mechanisms that facilitate the emergence of chicken-adapted avian influenza viruses (AIVs) from non-pathogenic duck-origin influenza viruses is crucial for improving AIV monitoring systems in poultry and controlling this disease. Amino acid deletions in the neuraminidase (NA) stalk domain serve as one of the molecular markers for AIV adaptation to Galliformes. This study highlights the critical role of <i>N</i>-glycosylation in the NA stalk domain in the pathogenesis of high pathogenicity avian influenza viruses in chickens. The findings propose a novel theory that the loss of glycosylation at the NA stalk domain, rather than a reduction in stalk length, is responsible for both NA function and increased virus pathogenicity in chickens.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0147824"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414597","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":"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":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915799/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conformational activation and disulfide exchange in HIV-1 Env induce cell-free lytic/fusogenic transformation and enhance infection.","authors":"Charles G Ang, Nadia L Hyatt, Giang Le Minh, Monisha Gupta, Manali Kadam, Philip J Hogg, Amos B Smith, Irwin M Chaiken","doi":"10.1128/jvi.01471-24","DOIUrl":"10.1128/jvi.01471-24","url":null,"abstract":"<p><p>Disulfide exchange is underexplored as a mechanism influencing HIV-1 entry. Prior studies demonstrated that redox enzyme inhibition can prevent HIV-1 infection but with limited mechanistic explanation. We hypothesize that ligand-driven rearrangement (\"conformational activation\") enables enzyme-mediated disulfide exchange in Env residues (\"disulfide trigger\") that promotes fusion transformations, enhancing virus entry. We tested soluble CD4 and CD4-binding site entry inhibitors as conformational activators and the ubiquitous redox enzyme thioredoxin-1 (Trx1) as disulfide trigger. We found that combination treatment caused fusion-like Env transformation and pseudovirus lysis, independent of cells. Notably, only compounds associated with gp120 shedding caused lysis when paired with Trx1. In each case, lysis was prevented by adding the fusion inhibitor T20, demonstrating that six-helix bundle formation is required as in virus-cell fusion. In contrast to conformationally activating ligands, neither the ground state stabilizer BMS-806 with Trx1 nor Trx1 alone caused lysis. Order of addition experiments reinforced conformational activation/disulfide trigger as a sequential process, with virus/activator preincubation transiently enhancing lysis and virus/Trx1 preincubation reducing lysis. Lastly, addition of exogenous Trx1 to typical pseudovirus infections exhibited dose-dependent enhancement of infection. Altogether, these data support conformational activation and disulfide triggering as a mechanism that can induce and enhance the fusogenic transformation of Env.IMPORTANCEHIV remains a global epidemic despite effective anti-retroviral therapies (ART) that suppress viral replication. Damage from early-stage infection and immune cell depletion lingers, as ART enables only partial immune system recovery, making prevention of initial virus entry preferable. In this study, we investigate disulfide exchange and its facilitating conformational rearrangements as underexplored, but critical, events in the HIV entry process. The HIV envelope (Env) protein effects cell entry by conformational rearrangement and pore formation upon interaction with immune cell surface proteins, but this transformation can be induced by Env's conformational activation and disulfide exchange by redox enzymes, which then integrates into established processes of HIV entry. The significance of this research is in identifying Env's conformational activation as a mechanistic requirement for initiating fusion by triggering disulfide exchange. This will aid the development of novel preventative strategies against HIV entry, particularly in the context of HIV-enhanced inflammation and comorbidities with redox mechanisms.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0147124"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256004","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":"Seneca Valley virus induces mitochondrial apoptosis by activating ER stress or the PERK pathway based on Ca²⁺ transfer from ER to mitochondria.","authors":"Lei Hou, Xiaoyu Yang, Changzhe Liu, Ju Yu, Zhi Wu, Yong Wang, Penghui Zeng, Jinshuo Guo, Yongyan Shi, Jianwei Zhou, Jue Liu","doi":"10.1128/jvi.02177-24","DOIUrl":"10.1128/jvi.02177-24","url":null,"abstract":"<p><p>Seneca Valley virus (SVV), also known as Senecavirus A, a porcine pathogen that causes vesicular diseases, is prevalent in pig herds worldwide. SVV infection induces endoplasmic reticulum (ER) stress in PK-15 and BHK-21 cells, accompanied by activation of the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6) pathways, which in turn facilitates SVV replication. ER stress is associated with the regulation of Ca²⁺ homeostasis and mitochondrial apoptosis. However, the precise role of Ca²⁺ in SVV-induced apoptosis remains unclear. In this study, western blotting, flow cytometry, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) detection revealed that either ER stress or the PERK pathway is involved in the apoptosis of SVV-infected cells treated with specific inhibitors. Furthermore, SVV-mediated ER stress markedly contributed to the transfer of Ca²⁺ from the ER to mitochondria. The subsequent increase in mitochondrial Ca²⁺ content was accompanied by an increased number of ER membranes near the mitochondria. Finally, the inhibition of mitochondrial Ca²⁺ overload, ER stress, and the PERK pathway substantially attenuated SVV-mediated mitochondrial dysfunction, as evidenced by analyzing mitochondrial membrane potential (MMP), mitochondrial permeability transition poremPTP, reactive oxygen speciesROS, and adenosine 5'-triphosphate ATP, and the levels of mitochondrial apoptosis. These findings demonstrate that SVV induces mitochondrial apoptosis, which is dependent on ER stress-mediated transmission of Ca²⁺ from the ER to the mitochondria.</p><p><strong>Importance: </strong>Viruses have developed multiple mechanisms to facilitate their proliferation or persistence through manipulating various organelles in cells. Seneca Valley virus (SVV), as a novel emerging pathogen associated with vesicular disease, is clinically and economically important infections that affect farm animals. Previously, we had confirmed that SVV-induced endoplasmic reticulum (ER) stress benefited for viral replication. Ca²⁺, as an intracellular signaling messenger mainly stored in the ER, is regulated by ER stress and then involved in apoptosis. However, the precise mechanism that Ca²⁺ transfer induced by SVV infection triggered apoptosis remained unclear. Here, we found that SVV infection triggered the Ca²⁺ transform from ER to mitochondria, resulting in mitochondrial dysfunction, and finally induced mitochondrial apoptosis. Our study shed light on a novel mechanism revealing how ER stress manipulates Ca²⁺ homeostasis to induce mitochondrial apoptosis and regulate viral proliferation.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0217724"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256018","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":"Zika virus inhibits cell death by inhibiting the expression of NLRP3 and A20.","authors":"Jian Li, Changyang Zhu, Yang Meng, Linliang Zhang, Cong Liu, Yali Qin, Mingzhou Chen","doi":"10.1128/jvi.01980-24","DOIUrl":"10.1128/jvi.01980-24","url":null,"abstract":"<p><p>Zika virus (ZIKV) is associated with microcephaly in neonates and neurological disorders in adults. Chronic ZIKV infection has been identified in the testes, indicating that the virus can lead to prolonged illness, yet its pathogenesis remains poorly understood. Here, we found that ZIKV infection does not induce significant cell death in mouse macrophages despite the critical role that cell death plays in the antiviral immune response. Furthermore, we discovered that ZIKV infection impairs the activation of the NLPR3-dependent inflammasome and inhibits apoptosis. Consequently, we investigated the regulatory mechanism of the NLRP3 inflammasome and apoptosis in the context of ZIKV infection. Our results revealed significant reductions in the protein expression levels of NLRP3 and A20, attributable to post-transcriptional or translational effects during ZIKV infection. These findings suggest that ZIKV infection may disrupt cell death pathways, leading to its pathogenicity.IMPORTANCEZika virus (ZIKV), first isolated from a nonhuman primate in Africa in 1947, was relatively understudied until 2016. By then, ZIKV had already been reported in more than 20 countries and territories. The infection poses a significant risk, as it is associated with microcephaly in infants and neurological disorders in adults; however, the underlying mechanisms responsible for these severe outcomes remain unclear. In this study, we demonstrate that ZIKV infection significantly reduces the expression of NLRP3 and A20 proteins through post-transcriptional or translational processes, which leads to inhibited cell death. These findings are critical because cell death plays a vital role in the host's antiviral immune response. Our findings highlight how ZIKV infection compromises essential cell death pathways, raising serious concerns about its pathogenesis. A comprehensive understanding of this disruption is vital for developing targeted interventions to mitigate the virus' impact on public health.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0198024"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458517","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":"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":"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":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915835/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"POLM inhibits porcine epidemic diarrhea virus replication by degrading multiple viral structural proteins.","authors":"Xinyu Cao, Yingyu Liu, Wu Tong, Wenzhen Qin, Xinyu Yang, Hai Yu, Hao Zheng, Wen Zhang, Guangzhi Tong, Ning Kong, Tongling Shan","doi":"10.1128/jvi.02278-24","DOIUrl":"10.1128/jvi.02278-24","url":null,"abstract":"<p><p>Porcine epidemic diarrhea, as a porcine epidemic diarrhea virus (PEDV)-induced infectious intestinal condition typified by diarrhea, emesis, dehydration, and anorexia, leads to death rates as high as 100% among suckling piglets. Given the existing commercial vaccines, it is essential to study host-virus interactions and formulate efficient anti-viral regimes. This study concerned a host factor POLM (a DNA polymerase family member) that exerts an anti-viral effect against PEDV proliferation. Our results indicated that POLM expression was increased following PEDV infection and was regulated by the transcription factor FOXA1. In addition, our findings indicated that POLM targeted and degraded PEDV structural proteins (N, S2, and M) by the autophagy pathway to inhibit PEDV proliferation. POLM could recruit the E3 ubiquitination ligase MARCH8 for N, S2, and M protein ubiquitination, which was subsequently recognized by p62, a cargo receptor, for translocation to the autophagic lysosome, therefore degrading the N, S2, and M proteins and preventing PEDV proliferation. In summary, we showed a novel therapeutic target for combating PEDV, i.e., using the POLM-MARCH8-p62-autophagosome pathway to degrade the PEDV N, S2, and M proteins.IMPORTANCEPEDV is a coronavirus that causes high mortality in piglets, which poses significant economic damage to swine farming. During PEDV infection, the host cells may promote the natural anti-viral immune response to suppress viral replication through a variety of potential host factors. In this study, we found upregulation of a host factor POLM by FOXA1 (a transcription factor) during PEDV infection. It was indicated that POLM could be a new anti-viral protein against the PEDV replication, which interacted with MARCH8 (an E3 ubiquitin ligase) and p62 (a cargo receptor) to facilitate the PEDV N, S2, and M protein degradation via the autophagy process. Apart from elucidating a previously unidentified anti-viral function of POLM, this study also provides a novel perspective for studying host anti-viral factors that act as regulators of anti-PEDV protein degrading pathways.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0227824"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382818","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":"The antiviral BDGR-49 provides protection from lethal, neurotropic Venezuelan equine encephalitis virus intranasal infection in mice.","authors":"Evan P Williams, Yi Xue, Peter Vogel, Dong Yang, Alejandro Ponce-Flores, Xiaoyu Li, Tyler J Ogorek, Manisha Saini, Jorge Iulek, Francesc Xavier Ruiz, Eddy Arnold, Jennifer E Golden, Bernd Meibohm, Colleen B Jonsson","doi":"10.1128/jvi.01679-24","DOIUrl":"10.1128/jvi.01679-24","url":null,"abstract":"<p><p>Venezuelan, western, and eastern equine encephalitis virus (VEEV, WEEV, and EEEV) cause a febrile illness that may result in fatal neurological disease in humans and equines. Human infections are typically from mosquito bites, although cases from respiratory exposure in laboratory accidents have been documented. In addition to natural mosquito-borne infection, the potential biothreat inherent in the ability to disseminate these viruses via the respiratory route has driven the development of antiviral drugs for this route of exposure. To address this gap, we tested the prophylactic administration of a novel brain-penetrant, antiviral, BDGR-49, against a lethal intranasal challenge of VEEV, WEEV, or EEEV in BALB/c mouse model. BDGR-49 conferred 100% protection with 6 mg kg^-1 twice per day for 6 days for VEEV, but not EEEV or WEEV. By 8 days post-infection (dpi), infectious virus, viral RNA, and viral antigen in the brain of BDGR-49-treated mice were significantly reduced. Brains of VEEV TrD-infected, BDGR-49-treated mice showed a significant reduction in the expression of genes associated with inflammation (<i>IFNB1</i>, <i>TNF</i>, <i>IL6</i>, and <i>CCL5</i>) and cell death (<i>CASP4</i>, <i>GSDMD</i>, <i>PYCARD</i>, and <i>ZBP1</i>). At dpi 14, histopathology showed that neuronal lesions and inflammatory cell infiltrates were essentially absent, and viral antigen was not detected in the brains of VEEV TrD-infected, BDGR-49-treated mice. In summary, although BDGR-49 treatment showed significant promise for the treatment of mice exposed intranasally to VEEV, the more rapid and efficient entry of EEEV and WEEV by this route into the central nervous system will require additional optimization of the dosing regimen.IMPORTANCEProphylactic and therapeutic treatment of viruses that cause encephalitis requires fast-acting drugs that rapidly penetrate the blood-brain barrier. Currently, clinicians have only a limited set of antivirals for the treatment of neurotropic infections such as herpesviruses or HIV-1, and none for alphaviruses, and treatment outcomes remain poor. New medical countermeasures will address the gap in treatment of viral encephalitis such as those caused by the neurotropic alphaviruses and others.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0167924"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11916738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399563","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}