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

Min LI¹Baichao Sun¹Jing Dong²Laurie J Minze¹Min Chen²Chao Cheng²Jin Wang^1*

• ¹Houston Methodist Research Institute, Houston, Texas, United States
• ²Baylor College of Medicine, Houston, Texas, United States

HIV integrates its proviral DNA into the host genome to establish persistent infection. To promote HIV clearance, we have designed an approach for selective elimination of host cells harboring replication-competent HIV (SECH), through inhibition of autophagy and anti-apoptotic molecules during viral reactivation. SECH approach can clear HIV-infected cells in approximately 50% humanized mice. However, the mechanisms for the resistance of reservoirs to depletion in mice with failure in HIV clearance are unclear. By single cell transcriptome analyses of T cell reservoirs resistant to SECH treatments, we found increases in pro-survival autophagy and glycolysis. Moreover, these resistant reservoirs expressed more epigenetic modifiers that repress HIV gene expression, while targeting such epigenetic repression promoted cell death in HIV-infected cells. These results indicate that T cell reservoirs refractory to depletion maintain a delicate balance between low levels of HIV gene expression and evasion of cell death. Our study suggests that targeting epigenetic repression of HIV is critical for the depletion of the viral reservoirs.