Suppression of HIV-1 transcription and latency reversal via ectopic expression of the viral antisense transcript AST.

Abstract

The mechanisms that regulate HIV-1 latency are not fully elucidated. Our previous studies showed that an HIV-1 antisense transcript (AST) promotes the deposition of histone modifications at the HIV-1 5' long terminal repeat, causing a closed chromatin state that suppresses viral transcription. Here, we report that ectopic expression of AST in CD4⁺ T cells from people living with HIV-1 undergoing antiretroviral therapy hinders the reactivation of viral transcription in response to ex vivo stimulation with pharmacologic and T cell receptor agonists, thus preventing the reversal of latency. We defined the structural domains and sequence motifs of AST that contribute to its latency-promoting functions. Last, we carried out an unbiased proteomic screen of AST interactors that revealed an array of host factors both previously known and not known to suppress HIV-1 expression. Our studies identify AST as a first-in-class biological molecule that is capable of enforcing HIV-1 latency and with actionable curative potential.