Project 3

University Of Alabama At Birmingham, Birmingham AL

Investigators

Abstract

There are over 38 million people living with HIV. Currently, there are highly effective and relatively safe treatments that suppress infection to undetectable levels and prevent transmission to others. However, these treatments must be taken for life, and they do not eradicate the virus from the body, they only prevent further rounds of productive virus replication. Under these circumstances a combination of latently infected and transcriptionally active cells remain resulting in viral rebound upon therapy interruption. The goal of an HIV CURE is to rid the body of all HIV-infected cells capable of re-initiating infection or to prevent their reactivation. Interestingly, Hansen, Picker et al. made the fundamental discovery that non-classical MHC-E responses can result in an HIV “cure” in up to 50% of SIV-infected non-human primates1-3. Notably, SIV-specific classical MHC-Ia restricted CD8+ T cell responses were absent in these animals creating a new paradigm for HIV vaccine development2, 3. While HIV downregulates expression of classical human MHC class I (HLA-Ia) molecules, HLA-E expression is enhanced on HIV-infected cells4. In addition, unlike the classical HLA-Ia locus, the HLA-E locus is non-polymporhic5. Thus, cell and gene therapy approaches that target HLA-E/HIV peptide complexes could offer increased HIV clearance and population wide coverage. Recently, the laboratories of our collaborators Drs. McMichael and Goepfert identified naturally occurring HIV-specific, HLA-E-restricted CD8+ T cells6, 7. These cells suppress HIV replication in vitro in patient derived HIV-infected CD4+ T cells6. Importantly, similar results were obtained when the T cell receptors (TCRs) from these cells were expressed in fresh CD8+ T cells providing in vitro validation that transduced CD8+ T cells can kill HIV-infected cells by recognizing HLA-E-HIV peptide complexes (HLA-E/HIV)6. Our preliminary data expands on these results demonstrating that autologous HLA-E/HIV TCR transduced CD8+ T cells efficiently reduce plasma viremia in humanized mice in the absence of antiretroviral therapy (ART). Our results also demonstrate that in humanized mice receiving ART, autologous HLA-E/HIV TCR transduced CD8+ T cells reduce HIV provirus DNA levels by a remarkable 50%. These data are provocative because they indicate that this innovative HLA-E based cell and gene therapy approach could have a significant impact on the state-of-the-art of the field by providing a novel path towards an HIV cure. In Project 3 we will test the overarching hypothesis that HLA-E-peptide complexes can be targets for antibodies, NK cells or CD8+ T cells to identify and mediate killing of HIV-infected cells and thus, clear HIV infection. Our objective is to evaluate if 1) HLA-E/HIV TCR transduced T cells can efficiently target HIV infection in macrophages, 2) combinations of HLA-E/HIV TCR transduced T cells will curtail the extraordinary ability of HIV to accumulate escape mutations, and 3) anti-HLA-E-peptide specific antibodies can enhance HIV suppression in vivo. The development of an HLA-E based cell and gene therapy approach is highly innovative, representing a significant improvement to current approaches by its “universal” nature.