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

 描述（由申请人提供）：与一般人群相比，HIV-1感染患者中几种类型癌症的发病率较高。关于这些观测的机械基础知之甚少。该R21提案解决了RFA-CA-15-013，特别是挑衅性问题2：“除了免疫功能障碍（包括炎症），HIV感染个体中差异癌症风险的HIV介导机制是什么？“我们将使用分子病毒学和分子生物学方法，以及生物信息学，来研究CD 4阳性T淋巴细胞的病毒感染与导致旁观者细胞中抗病毒APOBEC 3酶反式上调的信号传导机制之间的机制联系，导致基因组突变水平增加，从而导致癌症的可能性更高。这种机制的证明将是一个重大的进步，因为它是新颖的，并提出了多个治疗干预点。

 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.