Forging a Functional Cure for HIV: Transcription Regulators and Inhibitors

Abstract

Current antiretroviral therapy (ART) increases the survival of HIV-infected individuals, yet it is not curative. The major barrier to finding a definitive cure for HIV is our inability to identify and eliminate long-lived cells containing the dormant provirus, termed viral reservoir. When ART is interrupted, the viral reservoir ensures heterogenous and stochastic HIV viral gene expression, which can reseed infection back to pre-ART levels. While strategies to permanently eradicate the virus have not yet provided significant success, recent work has focused on the management of this residual viral reservoir to effectively limit comorbidities associated with the ongoing viral transcription still observed during suppressive ART, as well as limit the need for daily ART. Our group has been at the forefront of exploring the viability of the block-and-lock remission approach, focused on the long-lasting epigenetic block of viral transcription such that without daily ART, there is no risk of viral rebound, transmission, or progression to AIDS. Numerous studies have reported inhibitors of both viral and host factors required for HIV transcriptional activation. Here, we highlight and review some of the latest HIV transcriptional inhibitor discoveries that may be leveraged for the clinical exploration of block-and-lock and revolutionize the way we treat HIV infections.

Identification of aryl hydrocarbon receptor as a barrier to HIV-1 infection and outgrowth in CD4+ T cells

“…However, ART does not cure HIV-1, and immune competence is not restored. 1 , 2 Major barriers to HIV-1 remission/cure during ART include the persistence of viral reservoirs (VRs) in long-lived CD4 + T cells, 3 , 4 residual HIV-1 transcription, 5 – 7 and the non-restoration of mucosal CD4 + T cell-dependent intestinal barrier functions. 8 , 9 Subsequently, ART-treated PLWH experience chronic immune activation, immune metabolism deregulation, and increased risk for non-AIDS comorbidities, such as cardiovascular disease.…”

Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection

“…However, several evidences from the literature support the idea that the shock phase of the shock-and-kill approach to reverse HIV-1 latency may be achieved in the absence of NF-κB [ 27 ]. Moreover, other transcription factors have also been demonstrated to participate in HIV reactivation, resulting in a far more complicated process than the oversimplified LTR-driven transcription by NF-κB [ 28 , 29 ]. Finally, compensatory IKK regulatory mechanisms cannot be excluded [ 12 ].…”

A Canadian Survey of Research on HIV-1 Latency—Where Are We Now and Where Are We Heading?

“…In addition to the targeting strategies of the latent HIV-1 reservoir, the development of latency-modifying agents is an important therapeutic research axis. These agents comprise LRA, the “shock and kill” approach [ 141 ], and latency-promoting agents (LPAs), commonly associated with the “Block and Lock” approach [ 142 ], both associated with two HIV-1 curative strategies. There are significant and ongoing efforts in Canadian laboratories to screen and find LRA or LPA compounds.…”