Harnessing Highly Networked HLA-E-Restricted CTL Epitopes to Achieve a Broadly Effective HIV Cure

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ABSTRACT This proposal describes the framework of an Avant-Garde DP1 award for Dr. Gaurav Gaiha M.D. D.Phil. Dr. Gaiha is currently an Assistant Professor of Medicine at Harvard Medical School, Massachusetts General Hospital and the Ragon Institute of MGH, Harvard and MIT. Dr. Gaiha’s research is focused on leveraging an innovative approach known as structure-based network analysis towards the development of a functional HIV cure. This new methodology developed by Dr. Gaiha integrates network theory principles with protein structure data to identify mutation-resistant cytotoxic T cell (CTL) epitopes within the HIV proteome. These ‘highly networked’ epitopes were found to be preferentially targeted by individuals who naturally control HIV in the absence of therapy, setting the stage for translation of these findings into an effective, CTL-based vaccine for HIV. However, a major challenge to the development of a broad CTL-based vaccine is the highly polymorphic nature of MHC-Ia alleles (HLA A/B/C allomorphs) within the population at-large. Thus, this proposal intends to generate and test a vaccine candidate comprised of highly networked CTL epitopes restricted by the non- classical MHC-Ib HLA-E molecule, which is highly conserved among humans with only two known alleles. Our analyses of the HIV proteome have already identified five highly networked, HLA-E restricted HIV epitopes. To evaluate whether these epitopes can be harnessed into a novel vaccine, this proposal first seeks to leverage a novel mono-allelic HLA-E mouse developed using an innovative gene knock-in methodology. These animals will then be injected with a diverse set of multi-epitope immunogens comprised of HLA-E-restricted highly networked epitopes and assessed for the induction of de novo CTL responses in the presence and absence of drugs of abuse. The development of such a vaccine would have a major impact on the HIV epidemic as it would be broadly applicable to substance abusing populations who have reduced adherence and provide an economically feasible approach to achieve a functional HIV cure. Demonstrating the immunogenicity of a multi-networked HLA-E restricted epitope vaccine aims to overcome the obstacles associated with traditional approaches to therapeutic HIV vaccination and is consistent with the mission of both NIDA and the broader mission of the NIH.