Identification of immune signatures associated with HIV reservoir characteristics and clonal expansion

About This Grant

Abstract: During HIV infection, a reservoir of infected cells is formed that persists during antiretroviral therapy (ART). Although ART is effective at controlling viral replication, people with HIV (PWH) on ART still exhibit elevated levels of inflammation and immune dysfunction, suggesting ongoing immune damage from HIV infection. The mechanisms behind continued immune dysfunction in PWH on ART remain unclear, but it is possible that chronic immune stimulation by virally encoded RNAs and proteins contributes to this process. At the same time, activation and clonal expansion of infected CD4 T cells in response to interactions with cells and cytokines of the immune system contributes to the persistence of the HIV reservoir. Our hypothesis is that bidirectional stimulation between the reservoir and the immune system creates a self-perpetuating cycle that maintains both chronic inflammation and the persistence of infected cells in PWH on ART. If this hypothesis is correct, molecular pathways that contribute to reservoir/immune crosstalk could potentially be targeted to limit reservoir persistence and reservoir-induced pathology in PWH. The goal of this proposal is to comprehensively define the relationship between the immune system of PWH and the HIV reservoir through single-cell analysis of the transcriptome and proteome of immune cells across a large (n=125) cohort of ART suppressed PWH with well characterized HIV reservoirs. Additionally, we will quantify the clonality of the HIV reservoir for each individual and define immune signatures that are associated with clonal expansion of infected cells during ART. This combined dataset will allow us, for the first time, to perform a detailed correlational analysis of transcriptomic and proteomic signatures in the immune system with key reservoir characteristics (size, transcriptional activity and clonal expansion) across a large cohort of PWH. To achieve these goals, we will leverage a unique set of PBMC and plasma samples from 125 ART-suppressed PWH through our collaboration with Dr Sulggi Lee (UCSF), as well as cutting edge multiomic methods that are already established in the Browne lab. If this project is successful, it will generate the most detailed dataset to date describing molecular connections between the HIV reservoir and the immune system, and will suggest novel ways to interrupt the dynamics that drive reservoir persistence and pathogenesis in PWH on ART.