Promotion of HIV Clearance by Sensitization of HIV Reservoirs to Cell Death

HIV establishes persistent infection by integrating its proviral DNA into the host genome. To eliminate cells harboring replication-competent HIV, we developed an approach called SECH (Selective Elimination of Cells harboring HIV), which sensitizes HIV reservoirs to cell death by inhibiting autophagy and anti-apoptotic pathways during viral reactivation. SECH treatment cleared HIV in approximately 50 percent of humanized mice generated by transplanting human CD34+ stem cells into NSG-SGM3 mice (Hu-HSC mice). However, the reasons why some HIV reservoirs resist SECH-mediated clearance remained unknown.Using single-cell RNA sequencing of CD4+ T cells from Hu-HSC mice that failed to clear HIV following SECH treatment, we identified increased expression of genes involved in pro-survival autophagy, glycolysis, and epigenetic repression of HIV transcription. These resistant reservoirs maintained low levels of HIV expression while evading cell death. Targeting the epigenetic repression enhanced death of HIV-infected cells. These findings highlight that persistent HIV reservoirs resist clearance by balancing viral suppression and survival, and suggest that disrupting epigenetic repression may be key to eliminating them.