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The implementation of antiretroviral therapy 23 years ago has rendered HIV infection clinically manageable. However, the disease remains incurable, since it establishes latent proviral reservoirs, which in turn can stochastically begin reproducing viral particles throughout the patient's lifetime. Viral latency itself depends in large part on the silencing environment of the infected host cell, which can be chemically manipulated. “Shock and kill” therapy intends to reverse proviral quiescence by inducing transcription with pharmaceuticals and allowing a combination of antiretroviral therapy, host immune clearance and HIV-cytolysis to remove latently infected cells, leading to a complete cure. Over 160 compounds functioning as latency-reversing agents (LRAs) have been identified to date, but none of the candidates has yet led to a promising functional cure. Furthermore, fundamental bioinformatic and clinical research from the past decade has highlighted the complexity and highly heterogeneous nature of the proviral reservoirs, shedding doubt on the “shock and kill” concept. Alternative therapies such as the HIV transcription-inhibiting “block and lock” strategy are therefore being considered. In this review we describe the variety of existing classes of LRAs, discuss their current drawbacks and highlight the potential for combinatorial “shocktail” therapies for potent proviral reactivation. We also suggest investigating LRAs with lesser-known mechanisms of action, and examine the feasibility of “block and lock” therapy.
•The “shock and kill” method aims to cure HIV infection by reactivating and eliminating the latent proviral reservoir.•To date, “shock” compounds display a moderate reactivation of the proviruses, while oftentimes failing in the “kill” aspect.•This review suggests a thorough investigation into the use of different classes of LRAs in combinations.•The “kill” aspect of the therapy needs exhaustive research for improvement.•Alternative methodologies, such as the “block and lock”, are also reviewed.