Establishment of the SIV Reservoir and Mechanisms of Viral Rebound in Rhesus Monkeys

Abstract

ART leads to durable suppression of HIV-1 replication in the majority of individuals, but the persistent viral reservoir in resting memory CD4+ T cells is the key barrier to HIV-1 cure. In this thesis, we focus on the strategies to prevent the establishment of viral reservoir, as well as the cellular origins and the immunological signatures that lead to viral rebound. Broadly neutralizing antibodies (bNAbs) against HIV-1 Env are currently being developed for HIV-1 prevention. However, HIV-1 sequence diversity limits the prophylactic efficacy of bNAbs. In Chapter II, we evaluate the usage of bNAbs to prevent viral reservoir establishment in rhesus animals. We demonstrate that the V3 glycan-dependent antibody PGT121 alone and the V2 glycan-dependent antibody PGDM1400 alone both fail to protect against a mixed SHIV challenge. In contrast, the combination of both bNAbs provides 100% protection against this mixed SHIV challenge. These data reveal the importance of bNAb cocktails for the prevention of viral reservoir establishment. In Chapter III, we explore the origin and nature of the rebound virus in ART-suppressed, chronically SIV-infected rhesus monkeys following ART discontinuation. We sequenced putative replication-competent viral DNA from peripheral blood and lymph node mononuclear cells (PBMC and LNMC) during ART suppression, and compare to the rebound viral RNA after ART discontinuation. Sequences of initial rebound viruses closely matched viral DNA sequences in PBMC and LNMC during ART suppression, but recombinant viruses arose quickly after the initial rebound. These data suggest that intact proviral DNA in PBMC and LNMC during ART suppression is likely the direct origin of viral rebound in chronically SIV-infected rhesus monkeys following ART discontinuation. To further explore the immunological signatures at the time of ART discontinuation to predict viral rebound, we performed the transcriptomic analysis in a cohort of early ART-treated animals in Chapter IV. Together, these data suggest a critical interplay between the immune system and the viral reservoir, and has important implications for the design of next generation HIV cure strategies.