# Supplement to A Multi-omics Approach to Immune Responses in HIV Vaccination and Intervention

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $779,124

## Abstract

The parent P01 asks how HIV vaccines can expand T cells with unique functional capacities, including high
proliferative capacity, cytotoxic function, and memory features. We suggest that only T cells with such features
can provide the host with 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.
This supplement is requested to allow completing evaluation of a RhCMV/Ad26 strategy that provides samples
for the -omics analysis. The work was initiated using prior funding but additional funds are required for
evaluation of macaques already challenged and for vaccination of additional animals. This experiment uses a
unique Ad26 vector expressing a dominant-negative IL-10 receptor to boost unique immune responses to
RhCMV/SIV vaccines. The hypothesis is that inhibition of IL-10 signaling in APCs will create T cells with
unique functional capacities and simultaneously evade regulatory responses that are particularly strong...

## Key facts

- **NIH application ID:** 11005643
- **Project number:** 3P01AI178375-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** DENNIS J. HARTIGAN-O'CONNOR
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $779,124
- **Award type:** 3
- **Project period:** 2023-05-22 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11005643

## Citation

> US National Institutes of Health, RePORTER application 11005643, Supplement to A Multi-omics Approach to Immune Responses in HIV Vaccination and Intervention (3P01AI178375-02S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11005643. Licensed CC0.

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