Fig. 3.

‘Shock and Kill’ Strategies for HIV-1 Elimination. The idea of ‘shock and kill’ is to induce HIV-1 transcription from latently infected cells using LRAs followed by the virus- or immune-mediated cell death. Meanwhile, ART maintenance precludes new infections. Thus far, ‘shock and kill’ trials have seen limited success for HIV-1 reactivation and less on reducing viral reservoir sizes. To address these early failures, apoptosis inducers are being employed to ‘label’ HIV-1 reservoirs that are intrinsically resistant to cellular apoptosis and are joined with LRAs on selective elimination of infected cells. A combination of LRAs, along with CTLs and ADCCs, and antiretroviral induction could enhance viral elimination that is currently limited by the results of short drug half-lives, limited tissue penetration, and complex activities of multi-regimens. It is possible that multiple LRAs could be delivered as a single dosage. By targeting immune checkpoint inhibitors, the ‘kill’ or ultimate removal of reactivated viral reservoirs can be strengthened by therapeutic vaccines, bnAbs, CAR T cell therapy, and CTLs. HIV-1 reservoirs are less stable prior to ART intervention, likely due to a pro-inflammatory environment that favors T cell activation. Instead of conventional LRAs employed during suppressive HIV-1 infection, co-delivery of LRAs and ART during early infection may further disrupt the establishment of viral latency, minimize initial reservoir size, and ease viral elimination. These immune-linked events are operative through PI3K, PKC, RIG-1 and Smac pathways.