Targeting HIV-1 transcription: road to a cure?

Human Immunodeficiency Virus 1 (HIV-1) is the causative agent for acquired immunodeficiency syndrome (AIDS). Antiretroviral therapy has turned HIV-1 from a lethal disease to a chronic condition but is not curative due to the persistence of a small reservoir of latently infected cells. The molecular mechanisms driving HIV-1 latency have been extensively studied, thus far largely focusing on transcriptional regulation. Here, we summarize well established and newly discovered mechanisms of HIV-1 latency, as well as how studies of the HIV-1 promoter have informed the broader transcription field. As a strategy toward HIV-1 cure, latency reversal agents (LRAs) have been developed to pharmacologically target blocks in HIV-1 transcription to achieve reactivation of viral gene expression. However, clinical studies indicate that LRAs have largely failed to sufficiently activate the reservoir such that viral protein is produced, and there was no reduction in the size of the viral reservoir. Indeed it has become clear that co- and post-transcriptional mechanisms are also at play to regulate HIV-1 gene expression and may also serve as attractive targetable blocks. We also outline recent developments in technologies allowing the ex vivo characterization of the HIV-1 reservoir in people living with HIV (PWH). These novel technologies enable us to interrogate the different molecular compartments such as integrated intact and defective proviral HIV-1 DNA, unspliced and spliced RNA, and protein levels that provide unprecedented new insight into latency mechanisms. Lastly, the potential of different transcription-targeting cure strategies is discussed in light of the contributions of co- and posttranscriptional blocks and the advent of Long Acting (LA)-ART.