The HIV-1 Vpr R77Q mutant alters host apoptotic gene regulation in CD4+ T cells

HIV-1 viral protein R (Vpr) is a multifunctional protein central to HIV-1 pathogenesis and progression to AIDS. Polymorphisms in vpr have been linked to varying rates of HIV-1 progression. Of note is the HIV-1 Vpr R77Q mutant, associated with delayed progression to AIDS. We previously demonstrated that the R77Q mutant promotes a non-inflammatory, apoptotic phenotype in CD4+ T cells. To investigate the mechanism underlying the R77Q-induced apoptotic phenotype, we performed RNA sequencing on a CD4+ T cell line, HUT78, infected with either a replication-competent wild-type strain (NL4-3) or the R77Q mutant. Our results show that at 72 hours post-infection, transcriptomes were heterogeneous, and differential expression analysis identified 289 differentially expressed genes (DEGs) in the R77Q vs. WT comparison. Functional enrichment analysis revealed enriched pathways associated with apoptosis. Gene ontology (GO) terms and GO connections also revealed an apoptotic signature. Although both viral strains upregulated pro-apoptotic genes, the R77Q mutant failed to upregulate some key anti-apoptotic genes such as bcl-2, while WT-infected cells displayed upregulation of those anti-apoptotic genes. Predicted protein-protein interaction within the Bcl-2 family local network also suggests that interactions within this network were significantly different. Taken together, these findings provide a transcriptomic basis for our previous observations of enhanced apoptosis in R77Q-infected cells and highlight distinct host cell responses that may underlie delayed HIV-1 progression. These results may be useful in identifying new targets to delay AIDS progression.