Protective roles of CTL responses to HIV-1 associated self epitope

University Of California Los Angeles, Los Angeles CA

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Abstract

DESCRIPTION (provided by applicant): HLA-B*5701 is associated with slow progression to AIDS. While much attention has focused on the HLA- B*5701 restricted presentation of HIV-1 encoded epitopes to CD8+ T-cells, it remains unclear how HLA- B*5701 exerts it protective influence. In this proposal, we will explore the potential role of HLA-B*5701 presentation of self-epitopes derived from HIV-1 infected cells in controlling HIV-1 infection. Like other viruses, HIV-1 infection of a cell can increase the surface presentation of HLA-class I restricted self-epitopes. As part of the physiological response to stress, proteins become quickly up-regulated and degraded resulting in an altered repertoire of self-epitope presentation by the infected cell. While this phenomenon is well documented, the role played by presentation of self-epitopes in the overall immune response to HIV-1 infection and long-term protection of the host are completely unknown. The up-regulation of tumor-specific antigens, such as MART 1, is a process that has been capitalized upon for the design of therapeutic strategies. CD8+ T-cells from the cancer patient are cultured in vivo with autologous dendritic cells pulsed with peptides representing the tumor-specific epitope then infused back into the patient in an adoptive therapy strategy to augment ongoing CTL responses. Together these data indicate that further exploration is warranted into the role of self- epitopes in determining the rate of HIV-1 disease progression and as a potential target for therapeutic strategies to eradicate HIV-1 infected cells. Experiments within this proposal will test our hypothesis that CTL responses to self-antigens play a significant role in the overall long-term immunologic control of HIV-1 viremia by augmenting existing CTL responses to viral antigens. To test this hypothesis, we intend to: Aim 1) Characterize HLA-B*5701 restricted self-epitopes up-regulated by HIV-1 infection, Aim2) Investigate whether self epitopes, elicited by HIV-1 infection, generate HLA-restricted CTL in vivo, and Aim 3) Evaluate CTL functions of in vitro primed HLA-A*0201, and HLA-B*5701 restricted self-epitope-specific CD8+ T-cells by peptide pulsed monocyte derived dendritic cells. PUBLIC HEALTH RELEVANCE: The experiments could benefit HIV-1 infected individuals by providing a unique avenue for the development of therapeutic strategies.