Determining the impact of ultra-small SIV reservoirs on sustained ART-free remission

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Abstract/Summary Antiretroviral therapy (ART) effectively controls HIV replication, but it is not a cure. Therefore, considerable efforted is devoted to developing cure regimens that reduce viral reservoirs and boost antiviral immunity. These interventions seek to permit people with HIV (PWH) to stop ART and durably control HIV, inducing sustained ART-free remission. However, the virologic and immunologic determinants of ART-free remission are poorly understood. One of the enduring questions for HIV cure research is how far interventions must reduce viral reservoirs to attain clinically relevant periods of ART-free remission. The reservoir size at ART termination is anticipated to affect the time to viral rebound (TTR) and the capacity of antiviral immune responses to control virus replication. Yet, the association between reservoir size and TTR is unknown, and the immunologic basis of post-treatment viral control (PTC) is unclear. Nevertheless, it is challenging to address these fundamental questions in human clinical trials due to variability in patient groups and difficulty quantifying extremely small viral reservoirs in vivo. As a result, mathematical models have been developed to help guide and interpret HIV cure studies. These models agree that extremely small viral reservoirs are essential for HIV remission but differ in how remission can be achieved. Thus, to address these enduring questions, we developed a simian immunodeficiency virus (SIV)/rhesus macaque model that precisely sets the size of latent reservoirs in vivo. To do so, we infuse defined numbers of autologous in vitro generated SIV latently infected cells into ART-treated, SIV-naïve rhesus macaques. This model provides a level of precision and consistency in reservoir sizes that is difficult for other SIV models to match. Further, establishing reservoirs with genetically barcoded SIV permits stopping ART and determining TTR and the number of reactivating viruses. Therefore, we propose using this novel latency model to determine how progressively smaller SIV reservoirs affect TTR and PTC in the presence or absence of antiviral immunity. Specific Aim 1: Determine the TTR for defined SIV viral reservoirs. The goal of this Aim is to determine the TTR for increasingly small viral reservoirs in the absence of antiviral immunity. Specific Aim 2: Determine the impact of viral reservoir size and antiviral immunity on TTR and PTC. The goal of this Aim is to determine if latent reservoir size affects the ability of antiviral immunity to control infection after treatment interruption.