(PQ2) HIV INFECTION, APOBEC UPREGULATION, AND CANCER MUTAGENESIS

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 DESCRIPTION (provided by applicant): The incidence of several types of cancer is higher in HIV-1 infected patients in comparison to the general population. Little is known about the mechanistic basis for these observations. This R21 proposal addresses RFA-CA-15-013 and, specifically, provocative question 2: "Other than immune dysfunction (including inflammation), what are the HIV-mediated mechanisms that underlie differential cancer risk in individuals with HIV infection?" We will use molecular virology and molecular biology approaches, together with bioinformatics, to investigate a mechanistic link between viral infection of CD4-positive T lymphocytes and a signaling mechanism that causes the trans-upregulation of antiviral APOBEC3 enzymes in bystander cells, leading to increased levels of genomic mutation that in turn result in a higher likelihood of cancer. The demonstration of such a mechanism would be a significant advance because it is novel and suggests multiple points for therapeutic intervention.