Project 1

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ABSTRACT In order to effectively control HIV after ART is stopped, HIV-specific T cell responses to therapeutic vaccination must not only be increased in magnitude, but they also must be long- lived, have the capacity to home to sites of reservoir persistence, have the T cell memory-like capacity to robustly proliferate and execute effector functions in response to antigen (i.e., they need to overcome the residual T cell exhaustion that persists in pre-existing HIV-specific T cells despite viral load suppression with ART), and be refocused to have dominant responses that target vulnerable epitopes. Due to the limitations of standard T cell assays, and despite emerging data from clinical trials showing at least partial control of HIV post-vaccination, little is known about the mechanisms by which HIV therapeutic vaccine regimens transform ineffective pre-existing HIV-specific T cell immunity into an effective antiviral response. In this Project, we will leverage our experience performing integrated multi-modal systems immunology analysis with paired single cell transcriptome and TCR sequencing (scRNA/TCRseq) data and high- dimensional flow cytometry data. We will perform clonal-level analysis on HIV/SIV therapeutic vaccine-elicited CD8+ T cells from highly unique and clinically relevant human and macaque HIV/SIV cohorts in which therapeutic vaccines have exerted a measurable effect on altering viral load kinetics after treatment interruption to ask: to what extent are current top-candidate therapeutic vaccine regimens capable of recruiting new and/or pre-existing T cell clones with optimal memory-like properties (function and differentiation state; Aims 1 and 2), and to what extent do memory-like features (or other features) of the vaccine-elicited T cell response correlate with post-treatment control of HIV (Aim 3)? These studies will allow us to characterize in unprecedented depth the impact of different therapeutic vaccine regimens on critical – and previously unmeasurable – facets of the quality of the virus-specific T cell response. Our results will lay the groundwork for us to develop reliable measurements of virus-specific T cell clonal structure and differentiation state that will inform iterative studies in humans and macaques.