HIV Silencing and Cell Survival Signatures in Infected T cell Reservoirs

Rare CD4 T cells that harbor HIV under antiretroviral therapy (ART) represent an important barrier to HIV cure1-3, but the infeasibility of isolating and characterizing these cells in their natural state has led to uncertainty about whether they possess distinctive attributes that HIV cure-directed therapies might exploit. Here, we addressed this challenge using a microfluidic technology that isolates HIV-infected cell transcriptomes based solely on HIV DNA detection. HIV DNA+ memory CD4 T cells in blood from people receiving ART showed inhibition of six transcriptomic pathways including death receptor signaling, necroptosis signaling, and antiproliferative G12/13 signaling. Moreover, two groups of genes identified by network co-expression analysis were significantly associated with HIV DNA+ cells. These genes (n = 145) accounted for just 0.81% of the measured transcriptome and included negative regulators of HIV transcription that were higher in HIV DNA+ cells, positive regulators of HIV transcription that were lower in HIV DNA+ cells, and other genes involved in negative regulation of mRNA translation, additional RNA processing, and regulation of cell state and fate. These findings reveal HIV-infected memory CD4 T cells under ART as a distinctive population whose host transcriptomic patterns favor HIV silencing, cell survival, and cell proliferation, with important implications for the development of HIV cure strategies.