Prime, shock and kill: BCL-2 inhibition for HIV cure

Abstract

While modern HIV therapy can effectively suppress viral replication, the persistence of the latent reservoir posits the greatest hurdle to complete cure. The “shock and kill” strategy is under investigation for HIV therapy, aiming to reactivate latent HIV, and subsequently eliminate it through anti-retroviral therapy and host immune function. However, thus far, studies have yielded suboptimal results, stemming from a combination of ineffective latency reversal and poor immune clearance. Concomitantly, studies have now revealed the importance of the BCL-2 anti-apoptotic protein as a critical mediator of infected cell survival, reservoir maintenance and immune evasion in HIV. Furthermore, BCL-2 inhibitors are now recognized for their anti-HIV effects in pre-clinical studies. This minireview aims to examine the intersection of BCL-2 inhibition and current shock and kill efforts, hoping to inform future studies which may ultimately yield a cure for HIV.

Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4+ T-Cells by Decreasing Viral Release

“…This is consistent with the knowledge that metformin is used as an anti-aging medicine 83 . Most recent studies demonstrated the clinical benefits of Bcl-2 inhibitors (i.e., Venetoclax) in promoting VR purging [84][85][86][87] . Whether metformin supplementation of ART may render reactivated VR more sensitive to Bcl-2 blockade, requires investigations in animal models and human clinical trials.…”

Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1

“…Vesatolimod is thought to elicit this effect through a combination of increased viral expression after CD4 + T cell activation ( 25 ) and enhanced immune responses ( 24 ). Notwithstanding, induction of viral expression is insufficient for maximal reservoir clearance, and other hurdles may exist, such as immune exhaustion, immunosuppressive microenvironments, and up-regulation of prosurvival pathways, limiting immune-based clearance strategies ( 26 , 27 ). Therefore, cure strategies aimed at directly inducing intrinsic HIV-1–infected cell death may overcome barriers with host-mediated immune clearance approaches.…”

Advances in HIV Gene Therapy

“…The second approach aims to remove all viable latent virus from cell reservoirs, achieving an undetectable plasma load without needing ART [ 49 ], hence providing a sterilizing cure. This strategy is called the ‘Shock and Kill’ approach and has been studied extensively in early phase trial [ 50 , 51 , 52 ]. Although current forms of this cure approach do not employ gene therapy, it has been included in this review, in order to cover all current HIV cure approaches.…”