This work seeks to understand the basis for CD8 T cell receptor (TCR) recognition of HIV peptide antigens presented by human major histocompatibility complex class II (MHC II) proteins where normally CD8 T cells TCRs recognize antigen presented on MHC class 1. This work was prompted when a successful vaccination against SIV in non-human primates (NHP) demonstrated that in the vaccinated cohort CD8 T cells TCRs were recognizing SIV peptides presented on NHP MHC II and not MHC I. Such a finding raised the hypothesis that healthy uninfected CD8 T cells can usurp the role of virally depleted CD4 T cells during HIV infection to combat HIV. Subsequently Dr Bruce Walker's lab determined that the rare phenomenon of MHC II restricted CD8 T cells occurs in a small percent of human HIV non-progressors who have HIV but do not go on to develop AIDS. Typically these patients have MHC I protective alleles while MHC II HIV protective alleles has not been previously observed. We have partnered with Dr Bruce Walker's lab to determine the details of human HIV non-progressor CD8 TCR restriction to MHC II. We cloned and expressed the specific MHC II (DR11) and the clonal derived TCR from one of these patients. Uncommonly, in this patient's clonal CD8 T cells there are two TCR alpha chains and one shared beta chain. We demonstrated that only one TCR alpha beta (TRAV6) complex recognizes a specific HIV peptide presented by DR11 and that binding leads to T cell activation.
We aim to crystallize and solve the structures of these complexes to probe the essential molecular details of this TCR recognition. Additionally we aim to determine the role of the bystander TCR (TRAV26) alpha beta complex in this patients CD8 MHC II restriction. We have already shown that despite not recognizing DR11 presented HIV peptide, TRAV26 does activate T cells. As other TCRs and MHC II restriction arises, from other patient non-progressors, perhaps also with dual TCR alphas, we aim to encompass these into our studies. The longest a HIV non-progressor has survived post HIV infection without anti retro viral therapy is 30 + years. Understanding the mechanisms of how a CD8 T cell can co-opt the role of a CD4 cell in HIV infection could have a significant impact on HIV treatment and vaccine design.

Public Health Relevance

Over 35 million people are living with HIV/AIDS, yet there is no successful vaccine on the horizon to combat this pandemic. However, there are a small percent of people who have HIV yet do not develop AIDS. Some of these people have unusual cells in their immune system that may contribute to their ability to resist progression to AIDS. This project seeks to understand the nature of these cells and how they contribute to the immune response to HIV. Our goal is to gain novel insights into natural HIV control that will help improve HIV vaccine design.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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AIDS Molecular and Cellular Biology Study Section (AMCB)
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Church, Elizabeth S
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National Jewish Health
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Ranasinghe, Srinika; Lamothe, Pedro A; Soghoian, Damien Z et al. (2016) Antiviral CD8+ T Cells Restricted by Human Leukocyte Antigen Class II Exist during Natural HIV Infection and Exhibit Clonal Expansion. Immunity 45:917-930