This proposal is based on the hypothesis that control of HIV-1 disease progression in long-term survivors is primarily mediated by host cytotoxic T lymphocytes (CTL). These nonprogressors develop CD8+ memory CTL (CTLm) specific for the initial infecting HIV-1 species, and acquire CTLm with a broad array of specificity for quasispecies of HIV-1 that arise in the host. In contrast, most HIV-1-infected subjects fail to control HIV-1 replication, resulting in disease development characterized by high viral burden after the loss of anti-HIV-1 CTLm activity and inexorable decline in CD8+ T cells. The loss of anti-HIV-1 CTLm activity could be due to changes in the immunodominant regions of CTL epitopes of gp120 in variant quasispecies that result in immune escape. This escape may be caused by peptides that no longer bind to MHC Class I or peptides which bind to Class I but are no longer recognized by preexisting CTLm. Additionally, the variant peptides that bind to Class I epitopes. The investigator therefore proposes to determine the CTLm precursor frequency against predetermined and predicted epitopes using autologous HIV-1 Env V3-V5 peptides. These peptides will be derived from HIV-1 sequences of longitudinal samples of peripheral blood mononuclear cells of long-term nonprogressors and progressors from the Multicenter AIDS Cohort Study. He will also isolate and characterize the fine specificity of CD8+ CTL clones derived from the same longitudinal specimens against autologous HIV-1 Env V3-V5 peptides. Finally, he will delineate whether loss of Env-specific CTLm reactivity in progressors is related to (a) altered binding capacity of target Env peptides to MHC class I, and (b) antagonism of new variant peptides for CTL epitopes. This research will therefore address a fundamental issue in the immunobiology of HIV-1 infection, i.e., the role of quasispecies diversity and immune escape in HIV-1 disease progression. The results should be of importance to delineation of appropriate vaccine and therapeutic strategies for HIV-1 infection.
| Smith, Kellie N; Mailliard, Robbie B; Larsen, Brendan B et al. (2014) Dendritic cells restore CD8+ T cell reactivity to autologous HIV-1. J Virol 88:9976-90 |
| Melhem, Nada M; Smith, Kellie N; Huang, Xiao-Li et al. (2014) The impact of viral evolution and frequency of variant epitopes on primary and memory human immunodeficiency virus type 1-specific CD8? T cell responses. Virology 450-451:34-48 |
