Journal of Virology最新文献

{"title":"Seneca Valley virus 3C protease cleaves HDAC4 to antagonize type I interferon signaling.","authors":"Zijian Li, Jingjing Yang, Ruiyi Ma, Shijie Xie, Dan Wang, Rong Quan, Xuexia Wen, Jue Liu, Jiangwei Song","doi":"10.1128/jvi.02176-24","DOIUrl":"https://doi.org/10.1128/jvi.02176-24","url":null,"abstract":"<p><p>Seneca Valley virus (SVV) is a newly identified pathogen that poses a notable threat to the global pig industry. SVV has evolved multiple strategies to evade host antiviral innate immune responses. However, the underlying molecular mechanisms have not yet been fully elucidated. Histone deacetylases (HDACs) have been shown to function as host antiviral innate immune factors. In this study, we examined the mechanisms underlying SVV evasion of host innate immunity and found that SVV infection induced degradation and cleavage of HDAC4. Ectopic expression of HDAC4 suppressed SVV replication, whereas siRNA-mediated knockdown of HDAC4 enhanced SVV replication. Further studies showed that the viral 3C protease (3C^pro) degraded HDAC4 in a protease activity- and caspase pathway-dependent manner. In addition, 3C^pro cleaved HDAC4 at Q599, which blocked its ability to limit viral replication. We also found that HDAC4 interacted with the SVV viral RNA-dependent RNA polymerase 3D and induced its proteasomal degradation. The cleaved HDAC4 products did not block SVV replication or induce 3D degradation and did not induce type I interferon (IFN) activation and expression of IFN-stimulated genes (ISGs). Collectively, these findings identified HDAC4 as an antiviral factor with effects against SVV infection and provided mechanistic insights into how SVV 3C^pro antagonizes its function, which has implications for viral evasion of innate immunity.</p><p><strong>Importance: </strong>Seneca Valley virus (SVV) is an emerging pathogen that causes vesicular disease in pigs and poses a threat to the pork industry. Histone deacetylases (HDACs) are important in the regulation of innate immunity. However, little is known about their roles in SVV infection. Our results revealed HDAC4 as an anti-SVV infection factor that targets the viral RNA-dependent RNA polymerase, 3D, for degradation. The SVV proteinase 3Cpro targets HDAC4 for degradation and cleavage, and cleavage of HDAC4 abrogated its antiviral effect. HDAC4 promotes type I interferon (IFN) signaling, and SVV 3Cpro-mediated cleavage of HDAC4 antagonized induction of type I IFN and interferon-stimulated genes (ISGs). Our findings reveal a novel molecular mechanism by which SVV 3Cpro counteracts type I IFN signaling by targeting HDAC4.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0217624"},"PeriodicalIF":4.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382819","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":"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":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactions between human immunodeficiency virus and human endogenous retroviruses.","authors":"Mengying Li, Fengting Yu, Baoli Zhu, Jiang Xiao, Chang Yan, Xiaojie Yang, Xuelei Liang, Fang Wang, Hanxi Zhang, Fujie Zhang","doi":"10.1128/jvi.02319-24","DOIUrl":"https://doi.org/10.1128/jvi.02319-24","url":null,"abstract":"<p><p>Human immunodeficiency virus (HIV), a retrovirus of the Lentivirus genus, targets CD4⁺ T cells, causing immune dysfunction and AIDS. Approximately 8% of the human genome consists of human endogenous retroviruses (HERVs), ancient retroviral remnants that may interact with HIV. Despite antiretroviral therapy, challenges such as drug resistance, poor immune reconstitution (PIR), and reservoirs remain. This GEM discusses the impact of HIV on HERVs, the potential roles of HERVs in PIR and reservoirs, and provides insights into future research directions.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0231924"},"PeriodicalIF":4.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365187","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":"Distinct mutations emerge in the genome of serotype O foot-and-mouth disease virus during persistence in cattle.","authors":"Benedikt Litz, Leonie F Forth, Florian Pfaff, Martin Beer, Michael Eschbaumer","doi":"10.1128/jvi.01422-24","DOIUrl":"https://doi.org/10.1128/jvi.01422-24","url":null,"abstract":"<p><p>Like other RNA viruses, foot-and-mouth disease virus (FMDV) has a high mutation rate. After the acute phase of infection, about half of infected cattle develop a persistent FMDV infection that can last for weeks or months. During this persistent phase, the virus continues to replicate, resulting in the emergence of genomic heterogeneity. We have documented the pattern of mutations in the persistent phase by obtaining consensus-level sequences directly from oropharyngeal fluid (OPF) without prior virus isolation in culture. OPF samples were repeatedly collected from 22 experimentally infected cattle, 20 of which were virus positive in the OPF on day 21 after infection or later. We observed that during the persistent phase, the amount of non-synonymous mutations causing an amino acid change increased over time. Two amino acid changes that showed a striking increase during the persistent phase, VP3 A75T and VP2 Y79H, were present neither in the inoculum nor during the acute phase. Another amino acid change in VP3, R56C, which was previously implicated in FMDV pathogenicity, was already present in the inoculum and dominated toward the end of the trial in most samples. Several other amino acid changes occurred, particularly on the surface of VP2 around residue VP2 79. By functional analysis, we show that the persistent isolates evolve distinctly compared with cell culture adaptation but do not show signs of antigenic escape from neutralizing antibodies. In agreement with previous observations, we conclude that these amino acid changes are indeed associated with persistent infection of cattle with FMDV serotype O.</p><p><strong>Importance: </strong>Our research article describes the genetic changes that occur during the acute and persistent foot-and-mouth disease (FMDV) infection. This is of particular interest to understand viral dynamics within an infected population from which new viral strains could emerge. Especially FMDV, with its high antigenic diversity and very limited cross-reactivity between strains and serotypes, has already demonstrated in the past that new variants can quickly emerge and evade vaccine responses. In our study, we have observed that this dynamic evolution continues during the persistent phase. Persistently infected animals, which are clinically indistinguishable from healthy animals, also pose a reservoir for recombination. A better understanding of viral dynamics is essential for improved vaccines to prevent the emergence of antigenic variants.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0142224"},"PeriodicalIF":4.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365184","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":"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":"https://doi.org/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":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contrasting roles of PSGL-1 and PD-1 in regulating T-cell exhaustion and function during chronic viral infection.","authors":"Karla M Viramontes, Melissa N Thone, Jamie-Jean De La Torre, Emily N Neubert, Julia M DeRogatis, Chris Garcia, Monique L Henriquez, Roberto Tinoco","doi":"10.1128/jvi.02242-24","DOIUrl":"10.1128/jvi.02242-24","url":null,"abstract":"<p><p>Immune checkpoints are critical regulators of T-cell exhaustion, impairing their ability to eliminate antigens present during chronic viral infections. Current immune checkpoint inhibitors (ICIs) used in the clinic aim to reinvigorate exhausted T cells; yet, most patients fail to respond or develop resistance to these therapies, underscoring the need to better understand these immunosuppressive pathways. PSGL-1 (<i>Selplg</i>), a recently discovered immune checkpoint, negatively regulates T-cell function. We investigated the cell-intrinsic effects of PSGL-1, PD-1, and combined deletion on CD8⁺ T cells during chronic viral infection. We found that combined PSGL-1 and PD-1 (<i>Selplg^-/-Pdcd1^-/-</i>) deficiency in CD8⁺ T cells increased their frequencies and numbers throughout chronic infection compared to the wild type. This phenotype was primarily driven by PD-1 deficiency. Furthermore, while PD-1 deletion increased virus-specific T-cell frequencies, it was detrimental to their function. Conversely, PSGL-1 deletion improved T-cell function but resulted in lower frequencies and numbers. The primary mechanism behind these differences in cell maintenance was driven by proliferation rather than survival. Combined PSGL-1 and PD-1 deletion resulted in defective T-cell differentiation, driving cells from a progenitor self-renewal state to a more terminal dysfunctional state. These findings suggest that PD-1 and PSGL-1 have distinct, yet complementary, roles in regulating T-cell exhaustion and differentiation during chronic viral infection. Overall, this study provides novel insights into the individual and combined roles of PSGL-1 and PD-1 in CD8⁺ T-cell exhaustion. It underscores the potential of targeting these checkpoints in a more dynamic and sequential manner to optimize virus-specific T-cell responses, offering critical perspectives for improving therapeutic strategies aimed at reinvigorating exhausted CD8⁺ T cells.IMPORTANCEOur findings provide a comprehensive analysis of how the dual deletion of PD-1 and PSGL-1 impacts the response and function of virus-specific CD8⁺ T cells, revealing novel insights into their roles in chronic infection. Notably, our findings show that while PD-1 deletion enhances T-cell frequencies, it paradoxically reduces T-cell functionality. Conversely, PSGL-1 deletion improves T-cell function but reduces their survival. Whereas the combined deletion of PSGL-1 and PD-1 in CD8⁺ T cells improved their survival but decreased their function and progenitor-exhausted phenotypes during infection. We believe our study advances the understanding of immune checkpoint regulation in chronic infections and has significant implications for developing more effective immune checkpoint inhibitor (ICI) therapies.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0224224"},"PeriodicalIF":4.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256009","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":"Longitudinal analysis of rhesus macaque metabolome during acute SIV infection reveals disruption in broad metabolite classes.","authors":"Andrew Hudson, Peng Wu, Kyle W Kroll, Brady Hueber, Griffin Woolley, Pixu Shi, R Keith Reeves","doi":"10.1128/jvi.01634-24","DOIUrl":"https://doi.org/10.1128/jvi.01634-24","url":null,"abstract":"<p><p>Persons living with HIV experience significant metabolic dysregulation, frequently resulting in immune and other cellular dysfunction. However, our understanding of metabolism and its relationship to immunity in the context of HIV remains incompletely understood, especially as it relates to the acute and early chronic phases of HIV infection. Herein, we employed mass spectrometry and a simian immunodeficiency virus (SIV)-infected rhesus macaque model to characterize changes in over 500 plasma metabolites throughout SIV infection. This broad metabolomic approach recapitulated known pathogenic signatures of HIV, such as a perturbed tryptophan/kynurenine ratio, but also identified novel metabolic changes. We observed a general decrease in plasma amino acid concentrations, with the notable exceptions of elevated aspartate and glutamate. Acute infection was marked by a transient increase in lactate dehydrogenase activity, indicating a shift toward anaerobic metabolism. Indoleamine 2,3-dioxygenase activity, defined by the kynurenine/tryptophan ratio, was significantly increased in both acute and chronic phases and strongly correlated with viral load. These results provide a comprehensive characterization of metabolic fluctuations during early lentiviral infection, furthering our understanding of the crucial interplay between metabolism and immune response. Our findings highlight systemic metabolic consequences of infection and provide potential targets for therapeutic intervention or biomarkers of disease progression.</p><p><strong>Importance: </strong>Despite significant advances in antiretroviral therapy and pre-exposure prophylaxis, HIV remains a global challenge. Understanding the underlying immune mechanisms is critical for improving HIV control and therapeutic development. Cellular metabolism represents a crucial yet underappreciated area of immune system function. Metabolite availability and metabolic pathway preferences directly influence the functional response capacity of immune cells and are highly dysregulated during HIV infection. To further the understanding of metabolic impacts of HIV infection, we utilized cutting-edge mass spectrometry-based metabolome interrogation to measure over 500 metabolites using an acute simian immunodeficiency virus infection model in rhesus macaques. Our comprehensive analysis provides insights into the dynamic metabolic landscape throughout early infection, revealing both known and novel metabolic signatures. These findings enhance our understanding of the complex interplay between metabolism and immunity in lentiviral infections, potentially informing new strategies for early detection, prevention, and treatment of HIV.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0163424"},"PeriodicalIF":4.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256012","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":"Effect of host telomerase inhibition on human cytomegalovirus.","authors":"Chloe M Cavanaugh, Cora N Betsinger, Nicole Katchur, Sherry Zhang, Karen Yang, Maciej Nogalski, Ileana M Cristea, Daniel Notterman","doi":"10.1128/jvi.01578-24","DOIUrl":"https://doi.org/10.1128/jvi.01578-24","url":null,"abstract":"<p><p>Treatment options remain limited for human cytomegalovirus (HCMV). Host telomerase has been implicated in the pathogenesis and oncogenesis of multiple herpesviruses, most recently including HCMV. In this study, we investigated the effect of telomerase inhibition on HCMV replication, as well as the mechanism of the interaction between HCMV and host telomerase <i>in vitro</i>. We found that lytic HCMV infection increases host telomerase activity, at least in part, through modulation of hTERT expression during earlier phases of the HCMV replication cycle. We found telomerase inhibition strongly reduced viral titer for two HCMV strains in a dose-specific manner. Both post-translational pharmaceutical telomerase inhibition and siRNA-mediated knockdown of hTERT reduce HCMV yield. Telomerase inhibition results in both reduction of viral gene and protein expression across the HCMV replication cycle, and suppressed viral genome replication and viral infectivity, suggesting interference with at least early steps of the HCMV viral life cycle. Altogether, our findings indicate telomerase plays an important, perhaps non-canonical role in lytic HCMV infection which includes the support of viral replication and infectivity.</p><p><strong>Importance: </strong>Human cytomegalovirus (HCMV) seroprevalence and morbidity in immunocompromised patients and neonates infected <i>in utero</i> remain high globally. Host telomerase has been implicated in the success of multiple infection-induced pathologies, including the success of both lytic infection and oncogenesis in certain herpesviruses. The results of this study suggest a similar biologically important role for host telomerase in lytic HCMV infection. Furthermore, these results may provide the potential for a novel, adjunctive anti-viral treatment for HCMV infection as well as insight into the viral products likely to be involved with HCMV regulation of telomerase.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0157824"},"PeriodicalIF":4.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189658","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}