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Principal Investigator: Paul A. Goepfert
Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2020
Award: $662,144
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
HIV-1 sequence diversity presents a formidable obstacle in the development of an efficacious preventative or
therapeutic HIV-1 vaccine. Escape or adaptation from CD8 T cell mediated immune pressure is a major
contributor to viral diversity. An adapted epitope (AE) encodes an HLA class I (HLA-I) associated escape
mutation, while its counterpart non-adapted epitope (NAE) does not contain any evidence of HLA-I associated
mutation or CTL escape. We previously showed that infection with a highly adapted HIV-1 strain was associated
with a poor clinical outcome. The precise mechanism(s) responsible for this impaired viral control are not yet
understood and is the focus of this study. Although AE are poorly immunogenic in acute HIV infection and
following vaccination, our preliminary data show that CD8-AE are present during chronic HIV infection; however,
these CD8-AE are generally low avidity responses in both acute and chronic infection. Longitudinal sequence
analysis shows that these AEs do not undergo additional escape mutations or revert to the NAE form, despite
immune pressure from CD8-AE. Our preliminary data also demonstrated that low avidity immune responses can
induce a pro-inflammatory dendritic cell (DC) phenotype capable of trans-infecting CD4 T cells. Based on these
findings, our premise holds that poorly functioning CD8-AE are conferring a viral fitness advantage. Our
hypothesis is that CD8-AE contribute to HIV pathogenesis by failing to efficiently kill infected cells and thus
creating an inflammatory environment that promotes HIV proliferation in a DC-dependent manner. To test this
hypothesis, we will use samples obtained from humans (HIV infection and vaccination studies) and BLT-mice
infected with HIV, thereby performing complementary in vitro and in vivo studies. In aim 1, we will determine the
quality of CD8 T cell responses induced by NAE and AE. We will test the quality of CD8-NAE and AE-specific
responses by analyzing a cohort of patients with acute infection followed for 6 months off antiretroviral therapy
(ART) in addition to HIV seronegative individuals who received a mosaic vaccine encoding many AEs. In aim 2,
we will determine whether AE-specific CD8 T cells induce a pro- inflammatory DC phenotype that enhances CD4
T cell trans-infection. We will characterize and compare the ability of CD8-NAE and AE specific cells to induce
an inflammatory DC phenotype using samples obtained from acute infection and vaccination studies. Finally,
aim 3 will determine whether infection with HIV encoding AEs exacerbates acute phase viral load kinetics and
leads to an enhanced inflammatory state in an in-vivo humanized BLT mouse model. In summary, the role that
HIV adaptation plays in the function of CD8 T cells is relatively understudied. Our proposal will help determine
whether HIV specific CD8 T cells can be optimized to control viral infection and provide valuable information for
future vaccine prevention and cure strategies.
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Terms: <AIDS Virus><AIDS test><AIDS/HIV test><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Adoptive Transfer><Alleles><Allelomorphs><Antigen-Presenting Cells><Antigenic Determinants><Area><Assay><Avidity><BLT humanized mice><BLT humanized mouse><BLT mice><BLT mouse><Binding Determinants><Bioassay><Biologic Assays><Biological><Biological Assay><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cell Body><Cells><Chronic><Clinical><Cohort Analyses><Cohort Analysis><Data><Dendritic Cells><Development><Disease Progression><Effectiveness><Epitopes><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Future><Gamma interferon><Genetic Alteration><Genetic Change><Genetic defect><HIV><HIV Infections><HIV Seronegativities><HIV Seronegativity><HIV negative><HIV test><HIV vaccine><HIV-1><HIV-1 test><HIV-1 vaccine><HIV-2 test><HIV-I><HIV/AIDS Vaccines><HIV1><HIV1 vaccine><HTLV-III Infections><HTLV-III Seronegativities><HTLV-III Seronegativity><HTLV-III-LAV Infections><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><Human immunodeficiency virus test><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune><Immune Interferon><Immune Targeting><Immune response><Immune system><Immunes><Immunological response><Impairment><In Vitro><Individual><Infection><Inflammation><Inflammatory><Inflammatory Response><Interferon Gamma><Interferon Type II><Interferon-gamma><Kinetics><LAV-HTLV-III><LYT3><Light><Lymphadenopathy-Associated Virus><Mediating><Messenger RNA><Modern Man><Mosaicism><Mutation><Outcome><Pathogenesis><Patients><Phase><Phenotype><Photoradiation><Play><Prevention><Process><Receptors, Antigen, T-Cell, alpha-beta><Role><SEQ-AN><Sampling><Sequence Analyses><Sequence Analysis><Site><T cell response><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TcR alpha-beta><TcR αβ><Testing><Therapeutic><Vaccination><Vaccine Design><Vaccines><Veiled Cells><Viral><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Virus Diseases><Virus-HIV><Work><accessory cell><acute infection><allergic/immunologic body system><allergic/immunologic organ system><alpha-beta T-Cell Receptor><anti-retroviral therapy><anti-retroviral treatment><antiretroviral therapy><antiretroviral treatment><base><bone marrow liver and thymus mice><bone marrow liver and thymus mouse><bone marrow liver and thymus transplanted mice><bone marrow liver and thymus transplanted mouse><chronic infection><cohort><cross reactivity><developmental><flow cytophotometry><genome mutation><host response><human immunodeficiency virus vaccine><humanized mice><humanized mouse><immunogenic><immunoresponse><in vivo><inflammatory environment><inflammatory milieu><lFN-Gamma><mRNA><mosaic disorders><mouse model><murine model><new approaches><novel approaches><novel strategies><novel strategy><persistent infection><pressure><response><social role><vaccination study><vaccination trial><vaccine study><vaccine trial><viral fitness><viral infection><virus infection><virus-induced disease><αβ T-Cell Receptor>