Elucidation of the Mechanisms of CD8+ T Cell Noncytolytic Antiviral Response

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DESCRIPTION (provided by applicant): the infected cell. This type of noncytolytic suppression is called CD8+ T cell noncytolytic antiviral response (CNAR). The mechanisms of CNAR are as yet uncharacterized, but its importance is evidenced by CNAR's correlation with healthy clinical status in HIV-infected individuals. It has been a long-term goal of ours to discern the mechanisms of CNAR, so that we can learn how to elicit or mimic this response. The current research suggests that an unknown molecule or complex of molecules block HIV-1 replication at the initiation of virus transcription. We aim to analyze two branches of transcription regulation-host epigenetics and viral genetic elements-to identify the mechanisms of CNAR and the key molecules responsible. The proposed work will be focused on the hypothesis that CNAR induces transcriptional repressors such as histone deacetylases to suppress transcription from HIV-1 provirus; and that HIV-1 can mutate its genome to negate the effects of these transcriptional repressers. Preliminary data has shown that inhibiting histone deacetylation results in a decrease in CNAR; and that genetically-related HIV-1 isolates evolve differing sensitivities to CNAR over time. We will identify genetic elements that confer resistance by creating chimeric viruses between sensitive and resistant viruses. Also, we will use chromatin immunoprecipitation to examine the recruitment of histone deacetylase 1 and its effects on acetylation of core histones within the HIV-1 long terminal repeat of CD4+ T cells in CNAR suppression cultures. Our study will provide a better understanding of the molecules that mediate CNAR, the mechanisms of CNAR, and aid in developing novel antivirals that mimic or induce this immune response. The proposed research will define how CD8+ T cells suppress HIV-1 without killing the infected cell. Determining the mechanism of this immune response will provide a greater understanding of the host pathogen-interaction in HIV infection and potentially lead to the development of novel HIV therapeutics.