Transcriptional profiling of antigen-responding CD4 T cells from PLWH to antigenic stimulation or global T cell activation

Despite antiretroviral therapy (ART), HIV-1 persists in latently-infected CD4+ T cells, preventing cure. Antigen (Ag) drives proliferation of infected cells, preventing latent reservoir decay. However, the relationship between antigen recognition and HIV-1 gene expression is poorly understood since most studies of latency reversal use agents that induce non-specific global T cell activation. Here, we isolated rare CD4+ T cells responding to cytomegalovirus (CMV) or HIV-1 Gag antigens from participants on long-term ART and assessed T cell activation and HIV-1 RNA expression upon co-culture with autologous dendritic cells (DCs) presenting cognate antigens. Physiological presentation of cognate antigens induced broad T cell activation (median 42-fold increase in CD154+CD69+ cells) and significantly increased HIV-1 transcription (median 4-fold), mostly through the induction of rare cells with higher viral expression. Thus, despite low proviral inducibility, physiologic antigen recognition can promote HIV-1 expression, potentially contributing to spontaneous reservoir activity on ART and viral rebound upon ART interruption. Additionally, we observed striking differences in the transcriptome profiles of Ag-responding CD4+ T cells after stimulations with Ag or global T cell activators. This analysis revealed quantitative differences between NFAT and NFkB target genes and may guide future approaches to Ag-mediated HIV-1 latency reversal.