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

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Abstract/Summary Considerable efforted is devoted to developing HIV 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. Therefore, 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. It is a common assumption among the HIV research community that the size of HIV reservoirs at ART termination affects 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 forecast PTC and TTR after stopping ART. These models predict that viral reservoirs must contain hundreds to thousands of HIV latently infected cells to delay viral rebound for a few months, and the size of latent reservoirs dictates whether antiviral immune responses can control HIV replication after stopping ART. However, validating these predictions in PWH is challenging. Thus, to empirically test these predictions, we will use a simian immunodeficiency virus (SIV)/rhesus macaque model to precisely set the size of latent reservoirs in vivo. To do so, we will infuse defined numbers of autologous in vitro generated SIV latently infected cells into ART-treated, SIV-naïve rhesus macaques. Further, we will determine the number of latently infected cells that reactivate after stopping ART by establishing reservoirs with genetically barcoded SIV. Therefore, we will use 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. In this Aim, we will determine the TTR for viral reservoirs containing 5e4, 1e4, 1e3, and 1e2 latently infected cells. Specific Aim 2: Determine the impact of viral reservoir size and antiviral immunity on TTR and PTC. In this Aim, we will induce antiviral immunity with recombinant rhadinovirus encoding near full-length SIV and determine the TTR and viral loads post-ART for reservoirs containing 5e4 and 1e3 latently infected cells.