Abstract A reservoir of latently infected cells persists in various anatomical sites in people living with HIV (PLWH), despite effective virological control by antiretroviral therapy (ART). The majority of virally suppressed individuals experience rapid viral rebound upon ART interruption, providing a strong rationale for the development of cure strategies. Even in an ART-suppressed HIV infection, chronic inflammation and immune activation are observed, along with limited CD4+T cell reconstitution, mucosal immune dysfunction, co-morbidities, and accelerated ageing. Low-grade persistent transcription and trickling production of viral proteins from the pool of integrated proviruses are believed to be partly responsible for these conditions. HIV eradication strategies such as shock- and-kill have not been successful so far, and the pursuit of a functional cure or HIV remission has been thought as an alternative worth exploring. A functional cure entails long-term, durable control of viral expression in the absence of therapy, preventing disease progression and transmission, despite the presence of detectable integrated proviruses. Our group has been at the forefront of developing one such strategy, labeled the block- and-lock approach. The premise of this approach is that transcriptional inhibitors can mediate epigenetic silencing of proviral expression, locking the virus in a profound state of latency from which reactivation is very unlikely to occur upon ART discontinuation. We have demonstrated this principle using the small molecule didehydro-Cortistatin A (dCA) inhibitor of Tat, the key regulator of HIV transcriptional amplification. In in vitro and in humanized mouse models of HIV latency, dCA inhibition of HIV transcription over time drives the viral promoter into deep transcriptional inhibition, limiting viral reactivation upon treatment interruption or with latency reactivating agents (LRAs)1–8. We believe that HIV transcriptional inhibitors, in general, have the potential to transform the way we treat HIV- 1 infections. Here we propose to investigate the potential of adding the transcriptional inhibitor dCA to an ART regimen in the rhesus macaque (RhM) model of SHIV infection. Not only is dCA a new molecule that inhibits the activity of a viral target not yet clinically explored, but it also opens the possibility for exploration of novel approaches to fight HIV. Here we propose to: 1) determine the safety and pharmacokinetics of dCA in ART- treated RhMs; 2) understand the relationship between dCA treatment and reduction in viral RNA in tissues, with the time to viral rebound upon treatment interruption; and 3) study the impact of dCA as front-line therapy on the size of the established viral reservoir.