Optimal T-cell support for HIV neutralizing antibody induction to fusion peptide-inclusive regimens (Opti-FliP)

University Of California At Davis, Davis CA

Investigators

Abstract

This HIVRAD program will develop an HIV vaccine regimen that is based on cooperative interactions between Env fusion peptide (FP)-directed antibodies and follicle-homing helper and cytotoxic T cells. We will use innovative vaccine modalities and adjuvants that are designed to elicit high-quality T cells in support of anti-FP antibodies. Strategies for eliciting broadly neutralizing antibodies (bnAbs) against HIV have made substantial progress. There are indications that germline targeting, divided doses, mRNA vaccination, and other strategies may all contribute to the goal of reliably eliciting bnAbs in humans. If these strategies are successful, however, the elicited bnAbs will likely be of lower titer than required to protect against HIV. An effective vaccine will therefore elicit a concomitant high-quality T-cell response, in addition to bnAbs. The proposed research program combines investigation of cooperative antibody and T-cell responses in people with testing innovative tools for eliciting helper and cytotoxic T cells that are distinguished, not by magnitude, but rather by longevity, localization to B-cell follicles, functional effector functions and/or avidity. Project 1 will examine humoral responses and follicular T cells in human beings receiving combined SOSIP/HTI vaccines, and will examine the anti-FP responses that contribute to effective HIV neutralization in clade C-infected people. Project 2 will leverage IL-10 inhibitors to safely elicit high-quality CD8+ T cells—and will then selectively boost cells of higher avidity. Project 3 will use immunogens that are targeted to Tf cells and/or mucosal surfaces to elicit anti-FP bnAbs that are supported by high-intensity Tf responses. As a culmination, P3 will also integrate information from all program components to test a new “cooperative” vaccine regimen in macaques. A shared objective of our program is to test the influence of pre-existing Tf responses on humoral responses to vaccination, and examine if CD8+CXCR5+ T cells contribute meaningful helper function. A second major objective is to evaluate the importance of T-cell avidity for both follicular-helper and cytotoxic functions. A third collective goal is to understand how FP-directed antibodies contribute to protective breadth against clade-C HIV envelopes.