Multi-Omics Single-Cell Analysis Reveals Key Regulators of HIV-1 Persistence and Aberrant Host Immune Responses in Early Infection

The clearance of human immunodeficiency virus-1 (HIV-1) remains a significant public health challenge due to impaired cellular immune responses and HIV-1 maintenance during acute infection. However, the genetic and epigenetic changes influencing the immune response on host infected cells remain unclear. Here, this study analyzes HIV-1 infected CD4+ T cells from peripheral blood mononuclear cells from people living with HIV-1 (PLWH) during early infection (<6 months) using single-cell RNA and ATAC sequencing. It is observed that HIV-1 hinders the antiviral response, particularly by interfering with the interferon signaling pathway. Multimodal analysis identifies KLF2 as a key transcription factor in infected CD4+ T cells. Moreover, cells harboring HIV-1 provirus are predominantly identified as Th17 cells, which exhibit elevated KLF2 activity. This suggests an increased susceptibility to HIV-1 infection and a constrained immune response due to the quiescent characteristics of these cells. The finding provides insights into the immune mechanisms and key regulators of HIV-1 maintenance in CD4+ T cells during the early stages of infection.