{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T05:48:04Z","timestamp":1782712084104,"version":"3.54.5"},"reference-count":100,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>HIV-1 viral protein R (Vpr) is a multifunctional accessory protein that modulates host cellular pathways and contributes to viral pathogenesis. The HIV-1 Vpr R77Q polymorphism is enriched in long-term non-progressors (LTNPs) and has been associated with reduced overall cell death and a shift toward non-inflammatory apoptotic cell death in CD4+ T cells. However, the host mechanisms underlying this phenotype remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To define host responses to this variant, RNA sequencing was performed in the CD4+ T-cell line, HUT78, infected with replication-competent HIV-1 NL4\u20133 wild-type (WT) or the R77Q mutant across a time course of infection (4\u201372 hpi). Differential gene expression and functional enrichment analysis were complemented by functional assays, including mitochondrial membrane potential assessments, immunoblotting, and pharmacological and genetic modulation of the BCL-2 protein.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Comparison of infected and mock-treated cells revealed robust host transcriptional responses at early time points (4\u201324 hpi), consistent with known cellular responses to HIV-1 infection. While R77Q and WT infections showed minimal differences in host gene expression early post-infection, at 72 hpi 289 genes were differentially expressed at significant levels. WT infection induced anti-apoptotic programs, including upregulation of\n                      <jats:italic>BCL2<\/jats:italic>\n                      , whereas R77Q failed to activate these survival pathways. PPI analysis revealed a highly interconnected BCL-2 family-centered network governing intrinsic apoptosis. Functionally, R77Q infection resulted in significant mitochondrial depolarization, as evidenced by a JC-1 fluorescence shift indicating reduced mitochondrial membrane potential, consistent with activation of intrinsic apoptotic pathways. At the protein level, BCL-2 expression was significantly higher in WT compared to R77Q-infected cells. Modulation of BCL-2 confirmed its functional role: overexpression abrogated R77Q-induced apoptosis, whereas pharmacological inhibition with Venetoclax shifted WT-induced cell death from necrosis towards apoptosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings demonstrate that the R77Q mutant reprograms host apoptotic signaling by impairing BCL-2-mediated survival pathway and promoting mitochondrial dysfunction. This shift toward pro-apoptotic signaling may provide a mechanistic link between HIV-1 Vpr polymorphism and the LTNP phenotype.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1830094","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T05:40:35Z","timestamp":1782711635000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The HIV-1 Vpr R77Q mutant alters host apoptotic gene regulation in CD4+ T cells"],"prefix":"10.3389","volume":"16","author":[{"given":"Sidney T.","family":"Sithole","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Brigham YoungUniversity","place":["Provo, UT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Ramsey","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Brigham YoungUniversity","place":["Provo, UT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Macey C.","family":"Call","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Brigham YoungUniversity","place":["Provo, UT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth K. 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