Mohd. Shameel Iqbal

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.

Viruses have developed incredibly creative ways of making a virtue out of necessity, including taking full advantage of their small genomes. Indeed, viruses often encode multiple proteins within the same genomic region by using two or more reading frames in both orientations through a process called overprinting. Complex retroviruses provide compelling examples of that. The human immunodeficiency virus type 1 (HIV-1) genome expresses sixteen proteins from nine genes that are encoded in the three positive-sense reading frames. In addition, the genome of some HIV-1 strains contains a tenth gene in one of the negative-sense reading frames. The so-called Antisense Protein (ASP) gene overlaps the HIV-1 Rev Response Element (RRE) and the envelope glycoprotein gene, and encodes a highly hydrophobic protein of ~190 amino acids. Despite being identified over thirty years ago, relatively few studies have investigated the role that ASP may play in the virus lifecycle, and its expression in vivo is still questioned. Here we review the current knowledge about ASP, and we discuss some of the many unanswered questions.