In Vitro Tools to Study the Establishment of HIV-1 Latency and Evaluate Latency Reversing Agents for HIV-1 Cure Strategies
Open AccessHIV-1 establishes a latent reservoir in a subset of the cells it infects and there are no reliable known biomarkers to distinguish this population from uninfected cells. Antiretroviral therapy does not target this latent population; thus, it cannot cure HIV-1. Recent efforts in the field have focused on developing methods such as “Shock and Kill,” where latency reversing agents (LRAs) induce viral expression (the “shock”), allowing for elimination of these infected cells by viral cytopathicity or immune clearance (the “kill”). Thus far, no single LRA has been shown to reduce the latent reservoir in vivo. Further, it has been shown that the majority of the latent reservoir in vitro cannot be reactivated in the laboratory setting, and the mechanisms underlying what controls this inducibility are not fully understood. In order to reach an HIV-1 cure, the mechanisms underlying the generation of this uninducible reservoir must be studied, and alternative approaches to viral reactivation from latency must be explored. Here, we expand the TCM model of latency to study inducibility of intact proviruses and explore the mitochondrial antiviral signaling (MAVS) protein as a potential target for latency reversal. First, we demonstrated that the TCM model of latency can use R5 as well as non-B subtype viruses. Second, we demonstrated similitudes in the composition of intact and defective proviruses generated in this model to the reservoir found in people living with HIV-1 (PLWH), thus establishing that this system would be suitable for investigating factors controlling HIV-1 inducibility. Finally, we showed that triggering MAVS activation can reactivate HIV-1, suggesting this pathway can be exploited for shock and kill strategies.
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