Multi-omic understanding of the transformed host T-cell response to HIV following therapeutic vaccination

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Therapeutic HIV vaccines confront an immune system whose anti-pathogen responses are established and have usually been evolving for years. T-cell responses to immunodominant epitopes have been generated and may have been maintained—or could have forced viral escape and eventual expansion of T cells with alternative, originally sub-dominant specificities. Many HIV-specific T cells have low proliferative capacity, rendering them incapable of a robust response when antiretroviral treatment is stopped. Furthermore, the established T-cell repertoire failed to control acute infection, so expansion of pre-existing T cells with their attendant functional deficiencies is unlikely to be therapeutically effective. The primary goal of therapeutic vaccination must instead be expansion of new T-cell clones with superior function, and/or the restoration of function to pre-existing memory cells. We suggest that only such qualitative improvements can provide the host with new capacity for control over the virus. A central objective of our program is to understand the extent to which pre-existing host immune and metabolic features constrain the quality of T-cell responses to therapeutic vaccination. Which immunometabolic conditions predict and perhaps foster qualitatively superior responses? What fraction of the T-cell response to vaccination is represented by new and previously undetected clonotypes, and how do the functional capacities and differentiation of the new clonotypes differ from pre-existing ones? A second major objective is to evaluate the relative ability of different vaccine regimens and metabolic interventions to expand new HIV/SIV-specific T cells with stem-like qualities. We and others have shown that HIV-specific T cells in natural HIV controllers express high levels of the memory-promoting transcription factor, TCF-1, retain proliferative capacity, and exhibit metabolic plasticity. We hypothesize that vaccine- induced cells with stem-like properties often derive from naïve T-cell clonotypes not previously expanded or chronically exposed to antigen, and that different vaccine regimens differ in their ability to recruit such cells. A third and central objective of our effort is to learn how peptide specificity, stemness, and metabolic capacities of T cells responding to vaccination are related to control over viremia during ATI. A large literature supports our premise that high T-cell quality is required for control over viremia, and more specifically that T cell memory, or “stemness”, features are associated with effective host responses. However, these connections remain relatively unexplored in the context of therapeutic vaccination, in part due to scarcity of large therapeutic-vaccine studies that have yielded an appreciable efficacy signal. We will use samples from human and non-human primate therapeutic-vaccine studies that have shown evidence for T cell-mediated virologic suppression to understand if the T-cell features previously linked to control over infection are also typical of successful immune responses to therapeutic vaccines.