Frontiers in cellular and infection microbiology · 2026
The HIV-1 Vpr R77Q mutant alters host apoptotic gene regulation in CD4+ T cells.
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Sithole Sidney T, Ramsey Joshua, Call Macey C, Ewool Kenneth K K, Poole Brian D, Pickett Brett E, Berges Bradford K
Аннотация
INTRODUCTION: 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.
METHODS: To define host responses to this variant, RNA sequencing was performed in the CD4+ T-cell line, HUT78, infected with replication-competent HIV-1 NL4-3 wild-type (WT) or the R77Q mutant across a time course of infection (4-72 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.
RESULTS: Comparison of infected and mock-treated cells revealed robust host transcriptional responses at early time points (4-24 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 BCL2, 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.
DISCUSSION: 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.
METHODS: To define host responses to this variant, RNA sequencing was performed in the CD4+ T-cell line, HUT78, infected with replication-competent HIV-1 NL4-3 wild-type (WT) or the R77Q mutant across a time course of infection (4-72 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.
RESULTS: Comparison of infected and mock-treated cells revealed robust host transcriptional responses at early time points (4-24 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 BCL2, 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.
DISCUSSION: 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.