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. . .
HIV adaptation to CD8 T cell responses compromises immune responses during infection and is associated with poorer clinical outcomes. Using novel approaches, a unique cohort of newly infected patients, HIV vaccine recipients, and a humanized mouse model, we will determine the biological relevance of CD8 T cell mediated adaptation. These findings would be highly relevant for optimizing future HIV-1 vaccine designs for prevention and treatment.
