Epigenetic silencing and blockade of latency reversal by an HIV-1 encoded antisense transcript

The mechanisms that regulate human immunodeficiency virus 1 (HIV-1) latency are not fully elucidated. We reported that an HIV-1 antisense transcript (AST) induces epigenetic modifications at the HIV-1 promoter causing a closed chromatin state that suppresses viral transcription. Here we show that ectopic expression of AST in CD4+ T-cells from people with HIV-1 under antiretroviral therapy blocks latency reversal in response to pharmacologic and T-cell receptor stimulation, enforcing transcriptional silencing. We define structural domains and sequence motifs of AST contributing to its latency-promoting functions. Finally, we report an unbiased proteomics screen of AST interactors that revealed an array of previously known and potential new HIV-1-suppressive factors. Our studies identify AST as a first-in-class biological molecule capable of enforcing HIV-1 latency and with actionable curative potential.