Retrovirology最新文献

{"title":"Opposing roles of CLK SR kinases in controlling HIV-1 gene expression and latency.","authors":"Subha Dahal,&nbsp;Kiera Clayton,&nbsp;Terek Been,&nbsp;Raphaële Fernet-Brochu,&nbsp;Alonso Villasmil Ocando,&nbsp;Ahalya Balachandran,&nbsp;Mikaël Poirier,&nbsp;Rebecca Kaddis Maldonado,&nbsp;Lulzim Shkreta,&nbsp;Kayluz Frias Boligan,&nbsp;Furkan Guvenc,&nbsp;Fariha Rahman,&nbsp;Donald Branch,&nbsp;Brendan Bell,&nbsp;Benoit Chabot,&nbsp;Scott D Gray-Owen,&nbsp;Leslie J Parent,&nbsp;Alan Cochrane","doi":"10.1186/s12977-022-00605-4","DOIUrl":"https://doi.org/10.1186/s12977-022-00605-4","url":null,"abstract":"<p><strong>Background: </strong>The generation of over 69 spliced HIV-1 mRNAs from one primary transcript by alternative RNA splicing emphasizes the central role that RNA processing plays in HIV-1 replication. Control is mediated in part through the action of host SR proteins whose activity is regulated by multiple SR kinases (CLK1-4, SRPKs).</p><p><strong>Methods: </strong>Both shRNA depletion and small molecule inhibitors of host SR kinases were used in T cell lines and primary cells to evaluate the role of these factors in the regulation of HIV-1 gene expression. Effects on virus expression were assessed using western blotting, RT-qPCR, and immunofluorescence.</p><p><strong>Results: </strong>The studies demonstrate that SR kinases play distinct roles; depletion of CLK1 enhanced HIV-1 gene expression, reduction of CLK2 or SRPK1 suppressed it, whereas CLK3 depletion had a modest impact. The opposing effects of CLK1 vs. CLK2 depletion were due to action at distinct steps; reduction of CLK1 increased HIV-1 promoter activity while depletion of CLK2 affected steps after transcript initiation. Reduced CLK1 expression also enhanced the response to several latency reversing agents, in part, by increasing the frequency of responding cells, consistent with a role in regulating provirus latency. To determine whether small molecule modulation of SR kinase function could be used to control HIV-1 replication, we screened a GSK library of protein kinase inhibitors (PKIS) and identified several pyrazolo[1,5-b] pyridazine derivatives that suppress HIV-1 gene expression/replication with an EC₅₀ ~ 50 nM. The compounds suppressed HIV-1 protein and viral RNA accumulation with minimal impact on cell viability, inhibiting CLK1 and CLK2 but not CLK3 function, thereby selectively altering the abundance of individual CLK and SR proteins in cells.</p><p><strong>Conclusions: </strong>These findings demonstrate the unique roles played by individual SR kinases in regulating HIV-1 gene expression, validating the targeting of these functions to either enhance latency reversal, essential for \"Kick-and-Kill\" strategies, or to silence HIV protein expression for \"Block-and-Lock\" strategies.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"19 1","pages":"18"},"PeriodicalIF":3.3,"publicationDate":"2022-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9389714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9319973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR/Cas9 genome editing to create nonhuman primate models for studying stem cell therapies for HIV infection.","authors":"Jenna Kropp Schmidt, Matthew R Reynolds, Thaddeus G Golos, Igor I Slukvin","doi":"10.1186/s12977-022-00604-5","DOIUrl":"10.1186/s12977-022-00604-5","url":null,"abstract":"<p><p>Nonhuman primates (NHPs) are well-established basic and translational research models for human immunodeficiency virus (HIV) infections and pathophysiology, hematopoietic stem cell (HSC) transplantation, and assisted reproductive technologies. Recent advances in CRISPR/Cas9 gene editing technologies present opportunities to refine NHP HIV models for investigating genetic factors that affect HIV replication and designing cellular therapies that exploit genetic barriers to HIV infections, including engineering mutations into CCR5 and conferring resistance to HIV/simian immunodeficiency virus (SIV) infections. In this report, we provide an overview of recent advances and challenges in gene editing NHP embryos and discuss the value of genetically engineered animal models for developing novel stem cell-based therapies for curing HIV.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"19 1","pages":"17"},"PeriodicalIF":3.3,"publicationDate":"2022-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9363854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9276209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innate immune regulation in HIV latency models.","authors":"Rebecca M Olson,&nbsp;Germán Gornalusse,&nbsp;Leanne S Whitmore,&nbsp;Dan Newhouse,&nbsp;Jennifer Tisoncik-Go,&nbsp;Elise Smith,&nbsp;Christina Ochsenbauer,&nbsp;Florian Hladik,&nbsp;Michael Gale","doi":"10.1186/s12977-022-00599-z","DOIUrl":"https://doi.org/10.1186/s12977-022-00599-z","url":null,"abstract":"<p><strong>Background: </strong>Innate immunity and type 1 interferon (IFN) defenses are critical for early control of HIV infection within CD4 + T cells. Despite these defenses, some acutely infected cells silence viral transcription to become latently infected and form the HIV reservoir in vivo. Latently infected cells persist through antiretroviral therapy (ART) and are a major barrier to HIV cure. Here, we evaluated innate immunity and IFN responses in multiple T cell models of HIV latency, including established latent cell lines, Jurkat cells latently infected with a reporter virus, and a primary CD4 + T cell model of virologic suppression.</p><p><strong>Results: </strong>We found that while latently infected T cell lines have functional RNA sensing and IFN signaling pathways, they fail to induce specific interferon-stimulated genes (ISGs) in response to innate immune activation or type 1 IFN treatment. Jurkat cells latently infected with a fluorescent reporter HIV similarly demonstrate attenuated responses to type 1 IFN. Using bulk and single-cell RNA sequencing we applied a functional genomics approach and define ISG expression dynamics in latent HIV infection, including HIV-infected ART-suppressed primary CD4 + T cells.</p><p><strong>Conclusions: </strong>Our observations indicate that HIV latency and viral suppression each link with cell-intrinsic defects in specific ISG induction. We identify a set of ISGs for consideration as latency restriction factors whose expression and function could possibly mitigate establishing latent HIV infection.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"19 1","pages":"15"},"PeriodicalIF":3.3,"publicationDate":"2022-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9270781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10663112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive identification and characterization of the HERV-K (HML-9) group in the human genome.","authors":"Lei Jia, Mengying Liu, Caiqin Yang, Hanping Li, Yongjian Liu, Jingwan Han, Xiuli Zhai, Xiaolin Wang, Tianyi Li, Jingyun Li, Bohan Zhang, Changyuan Yu, Lin Li","doi":"10.1186/s12977-022-00596-2","DOIUrl":"10.1186/s12977-022-00596-2","url":null,"abstract":"<p><strong>Background: </strong>Human endogenous retroviruses (HERVs) result from ancestral infections caused by exogenous retroviruses that became incorporated into the germline DNA and evolutionarily fixed in the human genome. HERVs can be transmitted vertically in a Mendelian fashion and be stably maintained in the human genome, of which they are estimated to comprise approximately 8%. HERV-K (HML1-10) transcription has been confirmed to be associated with a variety of diseases, such as breast cancer, lung cancer, prostate cancer, melanoma, rheumatoid arthritis, and amyotrophic lateral sclerosis. However, the poor characterization of HML-9 prevents a detailed understanding of the regulation of the expression of this family in humans and its impact on the host genome. In light of this, a precise and updated HERV-K HML-9 genomic map is urgently needed to better evaluate the role of these elements in human health.</p><p><strong>Results: </strong>We report a comprehensive analysis of the presence and distribution of HERV-K HML-9 elements within the human genome, with a detailed characterization of the structural and phylogenetic properties of the group. A total of 23 proviruses and 47 solo LTR elements were characterized, with a detailed description of the provirus structure, integration time, potential regulated genes, transcription factor binding sites (TFBS), and primer binding site (PBS) features. The integration time results showed that the HML-9 elements found in the human genome integrated into the primate lineage between 17.5 and 48.5 million years ago (mya).</p><p><strong>Conclusion: </strong>The results provide a clear characterization of HML-9 and a comprehensive background for subsequent functional studies.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"19 1","pages":"11"},"PeriodicalIF":2.7,"publicationDate":"2022-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9178832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65721241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-inflammatory effects of recreational marijuana in virally suppressed youth with HIV-1 are reversed by use of tobacco products in combination with marijuana.","authors":"Li Yin,&nbsp;Ashok R Dinasarapu,&nbsp;Samiksha A Borkar,&nbsp;Kai-Fen Chang,&nbsp;Kristina De Paris,&nbsp;Julie J Kim-Chang,&nbsp;John W Sleasman,&nbsp;Maureen M Goodenow","doi":"10.1186/s12977-022-00594-4","DOIUrl":"https://doi.org/10.1186/s12977-022-00594-4","url":null,"abstract":"<p><strong>Background: </strong>Marijuana's putative anti-inflammatory properties may benefit HIV-associated comorbidities. How recreational marijuana use affects gene expression in peripheral blood cells (PBC) among youth with HIV-1 (YWH) is unknown.</p><p><strong>Approach: </strong>YWH with defined substance use (n = 54) receiving similar antiretroviral therapy (ART) were assigned to one of four analysis groups: YWH with detectable plasma HIV-1 (> 50 RNA copies/ml) who did not use substances (H+V+S-), and YWH with undetectable plasma HIV-1 who did not use substances (H+V-S-), or used marijuana alone (H+V-S+[M]), or marijuana in combination with tobacco (H+V-S+[M/T]). Non-substance using youth without HIV infection (H-S-, n = 25) provided a reference group. PBC mRNA was profiled by Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. Differentially expressed genes (DEG) within outcome groups were identified by Significance Analysis of Microarrays and used for Hierarchical Clustering, Principal Component Analysis, and Ingenuity Pathways Analysis.</p><p><strong>Results: </strong>HIV-1 replication resulted in > 3000 DEG involving 27 perturbed pathways. Viral suppression reduced DEG to 313, normalized all 27 pathways, and down-regulated two additional pathways, while marijuana use among virally suppressed YWH resulted in 434 DEG and no perturbed pathways. Relative to H+V-S-, multiple DEG normalized in H+V-S+[M]. In contrast, H+V-S+[M/T] had 1140 DEG and 10 dysregulated pathways, including multiple proinflammatory genes and six pathways shared by H+V+S-.</p><p><strong>Conclusions: </strong>YWH receiving ART display unique transcriptome bioprofiles based on viral replication and substance use. In the context of HIV suppression, marijuana use, alone or combined with tobacco, has opposing effects on inflammatory gene expression.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"19 1","pages":"10"},"PeriodicalIF":3.3,"publicationDate":"2022-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9151353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71434627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P-selectin glycoprotein ligand-1 (PSGL-1/CD162) is incorporated into clinical HIV-1 isolates and can mediate virus capture and subsequent transfer to permissive cells.","authors":"Jonathan Burnie,&nbsp;Arvin Tejnarine Persaud,&nbsp;Laxshaginee Thaya,&nbsp;Qingbo Liu,&nbsp;Huiyi Miao,&nbsp;Stephen Grabinsky,&nbsp;Vanessa Norouzi,&nbsp;Paolo Lusso,&nbsp;Vera A Tang,&nbsp;Christina Guzzo","doi":"10.1186/s12977-022-00593-5","DOIUrl":"https://doi.org/10.1186/s12977-022-00593-5","url":null,"abstract":"<p><strong>Background: </strong>P-selectin glycoprotein ligand-1 (PSGL-1/CD162) has been studied extensively for its role in mediating leukocyte rolling through interactions with its cognate receptor, P-selectin. Recently, PSGL-1 was identified as a novel HIV-1 host restriction factor, particularly when expressed at high levels in the HIV envelope. Importantly, while the potent antiviral activity of PSGL-1 has been clearly demonstrated in various complementary model systems, the breadth of PSGL-1 incorporation across genetically diverse viral isolates and clinical isolates has yet to be described. Additionally, the biological activity of virion-incorporated PSGL-1 has also yet to be shown.</p><p><strong>Results: </strong>Herein we assessed the levels of PSGL-1 on viruses produced through transfection with various amounts of PSGL-1 plasmid DNA (0-250 ng), compared to levels of PSGL-1 on viruses produced through infection of T cell lines and primary PBMC. We found that very low levels of PSGL-1 plasmid DNA (< 2.5 ng/well) were necessary to generate virus models that could closely mirror the phenotype of viruses produced via infection of T cells and PBMC. Unique to this study, we show that PSGL-1 is incorporated in a broad range of HIV-1 and SIV isolates and that virions with incorporated PSGL-1 are detectable in plasma from viremic HIV-1-infected individuals, corroborating the relevance of PSGL-1 in natural infection. Additionally, we show that PSGL-1 on viruses can bind its cognate selectin receptors, P-, E-, and L-selectins. Finally, we show viruses with endogenous levels of PSGL-1 can be captured by P-selectin and transferred to HIV-permissive bystander cells, highlighting a novel role for PSGL-1 in HIV-1 infection. Notably, viruses which contained high levels of PSGL-1 were noninfectious in our hands, in line with previous findings reporting the potent antiviral activity of PSGL-1.</p><p><strong>Conclusions: </strong>Our results indicate that levels of PSGL-1 incorporation into virions can vary widely among model systems tested, and that careful tailoring of plasmid levels is required to recapitulate physiological systems when using pseudovirus models. Taken together, our data suggest that PSGL-1 may play diverse roles in the physiology of HIV-1 infection, particularly due to the functionally active state of PSGL-1 on virion surfaces and the breadth of PSGL-1 incorporation among a wide range of viral isolates.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"19 1","pages":"9"},"PeriodicalIF":3.3,"publicationDate":"2022-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9123692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9180796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simon Litvak (1942–2022)","authors":"López-Lastra, Marcelo, Parissi, Vincent, Darlix, Jean-Luc","doi":"10.1186/s12977-022-00595-3","DOIUrl":"https://doi.org/10.1186/s12977-022-00595-3","url":null,"abstract":"&lt;p&gt;A talented Chilean-French biochemist, mentor to many brilliant students, with a unique scientific character, a friend who developed a strong collaborative research and teaching program between Chile and France.&lt;/p&gt;&lt;p&gt;Simon Litvak (Fig. 1) was born in the Chilean Coastal city and harbor of Valparaiso in 1942.&lt;/p&gt;&lt;figure&gt;&lt;figcaption&gt;&lt;b data-test=\"figure-caption-text\"&gt;Fig. 1&lt;/b&gt;&lt;/figcaption&gt;&lt;picture&gt;&lt;source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12977-022-00595-3/MediaObjects/12977_2022_595_Fig1_HTML.jpg?as=webp\" type=\"image/webp\"/&gt;&lt;img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"457\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12977-022-00595-3/MediaObjects/12977_2022_595_Fig1_HTML.jpg\" width=\"685\"/&gt;&lt;/picture&gt;&lt;p&gt;Simon Litvak a talented Chilean–French biochemist&lt;/p&gt;&lt;span&gt;Full size image&lt;/span&gt;&lt;svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"&gt;&lt;use xlink:href=\"#global-icon-chevron-right\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"&gt;&lt;/use&gt;&lt;/svg&gt;&lt;/figure&gt;&lt;p&gt;His initial focus was on protein synthesis in cell-free extracts, obtaining his professional degree in Biochemistry at the Faculty of chemistry and pharmacology of the University of Chile at Santiago (1965) [1, 2]. He then moved to Paris, France, to work under the supervision of François Chapeville on the biosynthesis of nucleic acids. Specifically, he worked on the 3′ end modification of the genomic RNA of the plant tymovirus Turnip yellow mosaic virus (TYMV), discovering that it was a substrate for the host enzyme tRNA nucleotidyltransferase, which added several nucleotides at the viral RNA 3′ end because the viral last 82 nucleotides folded into a tRNA-like structure [3, 4]. Along this line of research, Simon and collaborators found that the 3′ end domain of TYMV could be aminoacylated, causing a positive effect on the activity of the VIRAL REPLICASE [5]. He obtained his Ph.D. in Natural Sciences in 1972 from the University Paris VII. He then continued his work on the study of the interaction of viral RNAs and tRNA nucleotidyl transferases.&lt;/p&gt;&lt;p&gt;Soon after the discovery of reverse transcriptase in 1970, in 1975, Simon set up a research program on the plant DNA POLYMERASES [6,7,8] and on the famous retroviral DNA POLYMERASE, later called Reverse Transcriptase (RT) of avian myeloblastosis virus (AMV) [9,10,11,12,12] and the human immunodeficiency virus HIV [13,14,15,16].&lt;/p&gt;&lt;p&gt;Interestingly enough, DNA POLYMERASE A of the wheat germ was found to be active on RNA templates, in other words, to exhibit a reverse transcriptase activity [17].&lt;/p&gt;&lt;p&gt;A large amount of work was dedicated to the AMV and HIV RTs. In both cases, RTs were found to bind to the homologous RT tRNA initiator primer, namely tRNATrip for AMV RT and tRNALYS for HIV in a specific manner [15]. His work showed the role of viral RTs in the selection and positioning of the tRNA primer on the viral genomic RNA [12,13,14, 1","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"28 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2022-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138514979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"No evidence of bovine leukemia virus proviral DNA and antibodies in human specimens from Japan","authors":"Yamanaka, Meripet Polat, Saito, Susumu, Hara, Yukiko, Matsuura, Ryosuke, Takeshima, Shin-nosuke, Hosomichi, Kazuyoshi, Matsumoto, Yasunobu, Furuta, Rika A., Takei, Masami, Aida, Yoko","doi":"10.1186/s12977-022-00592-6","DOIUrl":"https://doi.org/10.1186/s12977-022-00592-6","url":null,"abstract":"The potential risk and association of bovine leukemia virus (BLV) with human remains controversial as it has been reported to be both positive and negative in human breast cancer and blood samples. Therefore, establishing the presence of BLV in comprehensive human clinical samples in different geographical locations is essential. In this study, we examined the presence of BLV proviral DNA in human blood and breast cancer tissue specimens from Japan. PCR analysis of BLV provirus in 97 Japanese human blood samples and 23 breast cancer tissues showed negative result for all samples tested using long-fragment PCR and highly-sensitive short-fragment PCR amplification. No IgG and IgM antibodies were detected in any of the 97 human serum samples using BLV gp51 and p24 indirect ELISA test. Western blot analysis also showed negative result for IgG and IgM antibodies in all tested human serum samples. Our results indicate that Japanese human specimens including 97 human blood, 23 breast cancer tissues, and 97 serum samples were negative for BLV.","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"16 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2022-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138514984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunoescape of HIV-1 in Env-EL9 CD8 + T cell response restricted by HLA-B*14:02 in a Non progressor who lost twenty-seven years of HIV-1 control","authors":"A. Moyano, Oscar Blanch-Lombarte, L. Tarancón-Díez, Núria Pedreño-Lopez, M. Arenas, Tamara Alvaro, C. Casado, I. Olivares, M. Vera, C. Rodríguez, J. del Romero, C. López-Galíndez, E. Ruiz-Mateos, J. Prado, M. Pernas","doi":"10.1186/s12977-022-00591-7","DOIUrl":"https://doi.org/10.1186/s12977-022-00591-7","url":null,"abstract":"","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"19 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2022-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65721172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIV-2/SIV Vpx antagonises NF-κB activation by targeting p65.","authors":"Douglas L Fink, James Cai, Matthew V X Whelan, Christopher Monit, Carlos Maluquer de Motes, Greg J Towers, Rebecca P Sumner","doi":"10.1186/s12977-021-00586-w","DOIUrl":"10.1186/s12977-021-00586-w","url":null,"abstract":"<p><strong>Background: </strong>The NF-κB family of transcription factors and associated signalling pathways are abundant and ubiquitous in human immune responses. Activation of NF-κB transcription factors by viral pathogen-associated molecular patterns, such as viral RNA and DNA, is fundamental to anti-viral innate immune defences and pro-inflammatory cytokine production that steers adaptive immune responses. Diverse non-viral stimuli, such as lipopolysaccharide and cytokines, also activate NF-κB and the same anti-pathogen gene networks. Viruses adapted to human cells often encode multiple proteins targeting the NF-κB pathway to mitigate the anti-viral effects of NF-κB-dependent host immunity.</p><p><strong>Results: </strong>In this study we have demonstrated using a variety of assays, in a number of different cell types including primary cells, that plasmid-encoded or virus-delivered simian immunodeficiency virus (SIV) accessory protein Vpx is a broad antagonist of NF-κB signalling active against diverse innate NF-κB agonists. Using targeted Vpx mutagenesis, we showed that this novel Vpx phenotype is independent of known Vpx cofactor DCAF1 and other cellular binding partners, including SAMHD1, STING and the HUSH complex. We found that Vpx co-immunoprecipitated with canonical NF-κB transcription factor p65, but not NF-κB family members p50 or p100, preventing nuclear translocation of p65. We found that broad antagonism of NF-κB activation by Vpx was conserved across distantly related lentiviruses as well as for Vpr from SIV Mona monkey (SIVmon), which has Vpx-like SAMHD1-degradation activity.</p><p><strong>Conclusions: </strong>We have discovered a novel mechanism by which lentiviruses antagonise NF-κB activation by targeting p65. These findings extend our knowledge of how lentiviruses manipulate universal regulators of immunity to avoid the anti-viral sequelae of pro-inflammatory gene expression stimulated by both viral and extra-viral agonists. Importantly our findings are also relevant to the gene therapy field where virus-like particle associated Vpx is routinely used to enhance vector transduction through antagonism of SAMHD1, and perhaps also through manipulation of NF-κB.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":"19 1","pages":"2"},"PeriodicalIF":3.3,"publicationDate":"2022-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8785589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9116421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}