RetrovirologyPub Date : 2024-02-29DOI: 10.1186/s12977-024-00637-y
Sergio P Alpuche-Lazcano, Robert J Scarborough, Anne Gatignol
{"title":"MicroRNAs and long non-coding RNAs during transcriptional regulation and latency of HIV and HTLV.","authors":"Sergio P Alpuche-Lazcano, Robert J Scarborough, Anne Gatignol","doi":"10.1186/s12977-024-00637-y","DOIUrl":"10.1186/s12977-024-00637-y","url":null,"abstract":"<p><p>Human immunodeficiency virus (HIV) and human T cell leukemia virus (HTLV) have replicative and latent stages of infection. The status of the viruses is dependent on the cells that harbour them and on different events that change the transcriptional and post-transcriptional events. Non-coding (nc)RNAs are key factors in the regulation of retrovirus replication cycles. Notably, micro (mi)RNAs and long non-coding (lnc)RNAs are important regulators that can induce switches between active transcription-replication and latency of retroviruses and have important impacts on their pathogenesis. Here, we review the functions of miRNAs and lncRNAs in the context of HIV and HTLV. We describe how specific miRNAs and lncRNAs are involved in the regulation of the viruses' transcription, post-transcriptional regulation and latency. We further discuss treatment strategies using ncRNAs for HIV and HTLV long remission, reactivation or possible cure.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10905857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139997323","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":"HERVK-mediated regulation of neighboring genes: implications for breast cancer prognosis.","authors":"Boying Liang, Tengyue Yan, Huilin Wei, Die Zhang, Lanxiang Li, Zengjing Liu, Wen Li, Yuluan Zhang, Nili Jiang, Qiuxia Meng, Guiyang Jiang, Yanling Hu, Jing Leng","doi":"10.1186/s12977-024-00636-z","DOIUrl":"10.1186/s12977-024-00636-z","url":null,"abstract":"<p><p>Human endogenous retroviruses (HERVs) are the remnants of ancient retroviral infections integrated into the human genome. Although most HERVs are silenced or rendered inactive by various regulatory mechanisms, they retain the potential to influence the nearby genes. We analyzed the regulatory map of 91 HERV-Ks on neighboring genes in human breast cancer and investigated the impact of HERV-Ks on the tumor microenvironment (TME) and prognosis of breast cancer. Nine RNA-seq datasets were obtained from GEO and NCBI SRA. Differentially expressed genes and HERV-Ks were analyzed using DESeq2. Validation of high-risk prognostic candidate genes using TCGA data. These included Overall survival (multivariate Cox regression model), immune infiltration analysis (TIMER), tumor mutation burden (maftools), and drug sensitivity analysis (GSCA). A total of 88 candidate genes related to breast cancer prognosis were screened, of which CD48, SLAMF7, SLAMF1, IGLL1, IGHA1, and LRRC8A were key genes. Functionally, these six key genes were significantly enriched in some immune function-related pathways, which may be associated with poor prognosis for breast cancer (p = 0.00016), and the expression levels of these genes were significantly correlated with the sensitivity of breast cancer treatment-related drugs. Mechanistically, they may influence breast cancer development by modulating the infiltration of various immune cells into the TME. We further experimentally validated these genes to confirm the results obtained from bioinformatics analysis. This study represents the first report on the regulatory potential of HERV-K in the neighboring breast cancer genome. We identified three key HERV-Ks and five neighboring genes that hold promise as novel targets for future interventions and treatments for breast cancer.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10885364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139935141","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}
RetrovirologyPub Date : 2024-02-12DOI: 10.1186/s12977-024-00635-0
Elliott S Chiu, Coby A McDonald, Roderick B Gagne, Henry Dunkleberger, Matthew Moxcey, Sue VandeWoude
{"title":"Endogenous feline leukemia virus long terminal repeat integration site diversity is highly variable in related and unrelated domestic cats.","authors":"Elliott S Chiu, Coby A McDonald, Roderick B Gagne, Henry Dunkleberger, Matthew Moxcey, Sue VandeWoude","doi":"10.1186/s12977-024-00635-0","DOIUrl":"10.1186/s12977-024-00635-0","url":null,"abstract":"<p><p>Endogenous retroviruses (ERV) are indicators of vertebrate evolutionary history and play important roles as homeostatic regulators. ERV long terminal repeat (LTR) elements may act as cis-activating promoters or trans-activating enhancer elements modifying gene transcription distant from LTR insertion sites. We previously documented that endogenous feline leukemia virus (FeLV)-LTR copy number variation in individual cats tracks inversely with susceptibility to virulent FeLV disease. To evaluate FeLV-LTR insertion characteristics, we assessed enFeLV-LTR integration site diversity in 20 cats from three genetically distinct populations using a baited linker-mediated PCR approach. We documented 765 individual integration sites unequally represented among individuals. Only three LTR integration sites were shared among all individuals, while 412 sites were unique to a single individual. When primary fibroblast cultures were challenged with exogenous FeLV, we found significantly increased expression of both exogenous and endogenous FeLV orthologs, supporting previous findings of potential exFeLV-enFeLV interactions; however, viral challenge did not elicit transcriptional changes in genes associated with the vast majority of integration sites. This study assesses FeLV-LTR integration sites in individual animals, providing unique transposome genotypes. Further, we document substantial individual variation in LTR integration site locations, even in a highly inbred population, and provide a framework for understanding potential endogenous retroviral element position influence on host gene transcription.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10863107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139723899","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}
RetrovirologyPub Date : 2024-01-23DOI: 10.1186/s12977-024-00633-2
Xiaowei Chen, Xiao Wang
{"title":"The HIV-1 gag p6: a promising target for therapeutic intervention.","authors":"Xiaowei Chen, Xiao Wang","doi":"10.1186/s12977-024-00633-2","DOIUrl":"10.1186/s12977-024-00633-2","url":null,"abstract":"<p><p>The p6 domain of the Gag precursors (Gag p6) in human immunodeficiency virus type 1 (HIV-1) plays multifunctional roles in the viral life cycle. It utilizes the endosomal sorting complex required for transport (ESCRT) system to facilitate viral budding and release from the plasma membrane through the interactions with the ESCRT-I component tumor susceptibility gene 101 (TSG101) and with the ALG-2 interacting protein X (ALIX). Moreover, Gag p6 contributes to viral replication by a range of posttranslational modifications such as SUMOylation, ubiquitination and phosphorylation. Additionally, Gag p6 also mediates the incorporation of the accessory protein Vpr into virions, thereby promoting Vpr-induced viral replication. However, less attention is focused on Gag p6 as therapeutic intervention. This review focuses on the structures and diverse functions of Gag p6 in viral replication, host cells, and pathogenesis. Additionally, several challenges were also discussed in studying the structure of Gag p6 and its interactions with partners. Consequently, it concludes that the Gag p6 represents an attractive target for the development of antiretroviral drugs, and efforts to develop p6-targeted antiretrovirals are expected to undergo significant growth in the forthcoming years.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10807055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139541955","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}
RetrovirologyPub Date : 2024-01-23DOI: 10.1186/s12977-024-00634-1
Natacha Faivre, Christel Verollet, Fabrice Dumas
{"title":"The chemokine receptor CCR5: multi-faceted hook for HIV-1.","authors":"Natacha Faivre, Christel Verollet, Fabrice Dumas","doi":"10.1186/s12977-024-00634-1","DOIUrl":"10.1186/s12977-024-00634-1","url":null,"abstract":"<p><p>Chemokines are cytokines whose primary role is cellular activation and stimulation of leukocyte migration. They perform their various functions by interacting with G protein-coupled cell surface receptors (GPCRs) and are involved in the regulation of many biological processes such as apoptosis, proliferation, angiogenesis, hematopoiesis or organogenesis. They contribute to the maintenance of the homeostasis of lymphocytes and coordinate the function of the immune system. However, chemokines and their receptors are sometimes hijacked by some pathogens to infect the host organism. For a given chemokine receptor, there is a wide structural, organizational and conformational diversity. In this review, we describe the evidence for structural variety reported for the chemokine receptor CCR5, how this variability can be exploited by HIV-1 to infect its target cells and what therapeutic solutions are currently being developed to overcome this problem.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10807162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139541998","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}
RetrovirologyPub Date : 2023-09-12DOI: 10.1186/s12977-023-00631-w
Charbel Akkawi, Jerome Feuillard, Felipe Leon Diaz, Khalid Belkhir, Nelly Godefroy, Jean-Marie Peloponese, Marylene Mougel, Sebastien Laine
{"title":"Murine leukemia virus (MLV) P50 protein induces cell transformation via transcriptional regulatory function.","authors":"Charbel Akkawi, Jerome Feuillard, Felipe Leon Diaz, Khalid Belkhir, Nelly Godefroy, Jean-Marie Peloponese, Marylene Mougel, Sebastien Laine","doi":"10.1186/s12977-023-00631-w","DOIUrl":"10.1186/s12977-023-00631-w","url":null,"abstract":"<p><strong>Background: </strong>The murine leukemia virus (MLV) has been a powerful model of pathogenesis for the discovery of genes involved in cancer. Its splice donor (SD')-associated retroelement (SDARE) is important for infectivity and tumorigenesis, but the mechanism remains poorly characterized. Here, we show for the first time that P50 protein, which is produced from SDARE, acts as an accessory protein that transregulates transcription and induces cell transformation.</p><p><strong>Results: </strong>By infecting cells with MLV particles containing SDARE transcript alone (lacking genomic RNA), we show that SDARE can spread to neighbouring cells as shown by the presence of P50 in infected cells. Furthermore, a role for P50 in cell transformation was demonstrated by CCK8, TUNEL and anchorage-independent growth assays. We identified the integrase domain of P50 as being responsible for transregulation of the MLV promoter using luciferase assay and RTqPCR with P50 deleted mutants. Transcriptomic analysis furthermore revealed that the expression of hundreds of cellular RNAs involved in cancerogenesis were deregulated in the presence of P50, suggesting that P50 induces carcinogenic processes via its transcriptional regulatory function.</p><p><strong>Conclusion: </strong>We propose a novel SDARE-mediated mode of propagation of the P50 accessory protein in surrounding cells. Moreover, due to its transforming properties, P50 expression could lead to a cellular and tissue microenvironment that is conducive to cancer development.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10496198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10232104","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}
RetrovirologyPub Date : 2023-08-22DOI: 10.1186/s12977-023-00629-4
Joy Twentyman, Anthony Khalifeh, Abby L Felton, Michael Emerman, Molly Ohainle
{"title":"Primate TRIM34 is a broadly-acting, TRIM5-dependent lentiviral restriction factor.","authors":"Joy Twentyman, Anthony Khalifeh, Abby L Felton, Michael Emerman, Molly Ohainle","doi":"10.1186/s12977-023-00629-4","DOIUrl":"10.1186/s12977-023-00629-4","url":null,"abstract":"<p><p>Human immunodeficiency virus (HIV) and other lentiviruses adapt to new hosts by evolving to evade host-specific innate immune proteins that differ in sequence and often viral recognition between host species. Understanding how these host antiviral proteins, called restriction factors, constrain lentivirus replication and transmission is key to understanding the emergence of pandemic viruses like HIV-1. Human TRIM34, a paralogue of the well-characterized lentiviral restriction factor TRIM5α, was previously identified by our lab via CRISPR-Cas9 screening as a restriction factor of certain HIV and SIV capsids. Here, we show that diverse primate TRIM34 orthologues from non-human primates can restrict a range of Simian Immunodeficiency Virus (SIV) capsids including SIV<sub>AGM-SAB</sub>, SIV<sub>AGM-TAN</sub> and SIV<sub>MAC</sub> capsids, which infect sabaeus monkeys, tantalus monkeys, and rhesus macaques, respectively. All primate TRIM34 orthologues tested, regardless of species of origin, were able to restrict this same subset of viral capsids. However, in all cases, this restriction also required the presence of TRIM5α. We demonstrate that TRIM5α is necessary, but not sufficient, for restriction of these capsids, and that human TRIM5α functionally interacts with TRIM34 from different species. Finally, we find that both the TRIM5α SPRY v1 loop and the TRIM34 SPRY domain are essential for TRIM34-mediated restriction. These data support a model in which TRIM34 is a broadly-conserved primate lentiviral restriction factor that acts in tandem with TRIM5α, such that together, these proteins can restrict capsids that neither can restrict alone.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10212267","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}
RetrovirologyPub Date : 2023-08-21DOI: 10.1186/s12977-023-00630-x
Merle Flecks, Nicole Fischer, Jacomina Krijnse Locker, Ralf R Tönjes, Antonia W Godehardt
{"title":"Analysis of PERV-C superinfection resistance using HA-tagged viruses.","authors":"Merle Flecks, Nicole Fischer, Jacomina Krijnse Locker, Ralf R Tönjes, Antonia W Godehardt","doi":"10.1186/s12977-023-00630-x","DOIUrl":"10.1186/s12977-023-00630-x","url":null,"abstract":"<p><strong>Background: </strong>Using pigs as organ donors has advanced xenotransplantation to the point that it is almost ready for clinical use. However, there is still a zoonotic risk associated with xenotransplantation, and the potential transmission of porcine endogenous retroviruses needs to be surveyed. Despite significant attempts to eliminate this risk, by the selection of PERV-C free pigs with low expression of PERV-A, -B, and by the genome-wide inactivation of PERV using CRISPR/Cas9, the impact of superinfection resistance (SIR) was not investigated. SIR is a viral trait that prevents reinfection (superinfection). For PERV, the underlying mechanism is unclear, whether and how cells, that harbor functional PERV, are protected. Using PERV-C(5683) as a reference virus, we investigated SIR in a newly developed in vitro model to pursue the mechanism and confirm its protective effect.</p><p><strong>Results: </strong>We developed three PERV-C constructs on the basis of PERV-C(5683), each of which carries a hemagglutinin tag (HA-tag) at a different position of the envelope gene (SP-HA, HA-VRA, and RPep-HA), to distinguish between primary infection and superinfection. The newly generated PERV-C(5683)-HA viruses were characterized while quantifying the viral RNA, reverse transcriptase activity, protein expression analysis, and infection studies. It was demonstrated that SP-HA and RPep-HA were comparable to PERV-C(5683), whereas HA-VRA was not replication competent. SP-HA and RPep-HA were chosen to challenge PERV-C(5683)-positive ST-IOWA cells demonstrating that PERV-C-HA viruses are not able to superinfect those cells. They do not integrate into the genome and are not expressed.</p><p><strong>Conclusions: </strong>The mechanism of SIR applies to PERV-C. The production of PERV-C particles serves as a defense mechanism from superinfection with exogenous PERV-C. It was demonstrated by newly generated PERV-C(5683)-HA clones that might be used as a cutting-edge tool. The HA-tagging of PERV-C is novel, providing a blueprint for the tagging of other human tropic PERV viruses. The tagged viruses are suitable for additional in vitro and in vivo infection studies and will contribute, to basic research on viral invasion and pathogenesis. It will maintain the virus safety of XTx.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10209034","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}
RetrovirologyPub Date : 2023-08-10DOI: 10.1186/s12977-023-00628-5
Rachel M Podgorski, Jake A Robinson, Mandy D Smith, Suvadip Mallick, Huaqing Zhao, Ronald S Veazey, Dennis L Kolson, Katharine J Bar, Tricia H Burdo
{"title":"Transmitted/founder SHIV.D replicates in the brain, causes neuropathogenesis, and persists on combination antiretroviral therapy in rhesus macaques.","authors":"Rachel M Podgorski, Jake A Robinson, Mandy D Smith, Suvadip Mallick, Huaqing Zhao, Ronald S Veazey, Dennis L Kolson, Katharine J Bar, Tricia H Burdo","doi":"10.1186/s12977-023-00628-5","DOIUrl":"10.1186/s12977-023-00628-5","url":null,"abstract":"<p><p>A biologically relevant non-human primate (NHP) model of HIV persistence in the central nervous system (CNS) is necessary. Most current NHP/SIV models of HIV infection fail to recapitulate viral persistence in the CNS without encephalitis or fail to employ viruses that authentically represent the ongoing HIV-1 pandemic. Here, we demonstrate viral replication in the brain and neuropathogenesis after combination antiretroviral therapy (ART) in rhesus macaques (RMs) using novel macrophage-tropic transmitted/founder (TF) simian-human immunodeficiency virus SHIV.D.191,859 (SHIV.D). Quantitative immunohistochemistry (IHC) and DNA/RNAscope in situ hybridization (ISH) were performed on three brain regions from six SHIV.D-infected RMs; two necropsied while viremic, two during analytical treatment interruptions, and two on suppressive ART. We demonstrated myeloid-mediated neuroinflammation, viral replication, and proviral DNA in the brain in all animals. These results demonstrate that TF SHIV.D models native HIV-1 CNS replication, pathogenesis, and persistence on ART in rhesus macaques.</p>","PeriodicalId":21123,"journal":{"name":"Retrovirology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10209802","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}