Shock-and-kill versus block-and-lock: Targeting the fluctuating and heterogeneous HIV-1 gene expression

Abstract

Despite effective antiretroviral therapy, HIV-1 persistence in the latent reservoir remains the major barrier to cure. Current strategies for HIV-1 eradication require either inducing HIV-1 expression to expose latently infected cells for immune clearance [known as the “shock-and-kill strategy” (1)] or silencing HIV-1 expression for a prolonged drug-free remission [known as the “block-and-lock strategy” (2)]. Extensive small-molecule compound library screens have identified drugs that can reactivate HIV-1 from latency [known as latency-reversing agents (LRAs) (1)] as well as drugs that can reduce HIV-1 expression [known as HIV-1−suppressing agents (3) or latency-promoting agents (LPAs) (4)]. However, none of these agents have reached a durable HIV-1 remission in clinical trials, suggesting that more drug candidates should be identified and tested. Lu et al. (5) performed a drug screen to identify compounds that can modulate the fluctuations of HIV-1 gene expression. Gene expression does not always follow deterministic kinetics like an on/off switch: Instead, gene expression levels frequently fluctuate (“noise”), creating stochastic variations in cell fate determination (6). For example, if HIV-1 gene expression is deterministic, maximum T cell activation should be able to reactivate all HIV-1 proviruses from latency. However, ex vivo studies showed that each round of maximum T cell activation can only reactivate a subset of HIV-1 expression (7). This is because HIV-1 gene expression level is determined by the stochastic fluctuation of Tat expression (8). The fluctuation and stochastic nature of HIV-1 gene expression creates a barrier for effective HIV-1 eradication … [↵][1]1To whom correspondence may be addressed. Email: ya-chi.ho{at}yale.edu. [1]: #xref-corresp-1-1