(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 感染患者中几种癌症的发病率更高。人们对这些观察结果的机制基础知之甚少。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）之外，HIV 感染者的不同癌症风险背后的 HIV 介导机制是什么？”我们将利用分子病毒学和分子生物学方法以及生物信息学，研究 CD4 阳性 T 淋巴细胞的病毒感染与导致旁观者细胞中抗病毒 APOBEC3 酶反式上调的信号传导机制之间的机制联系，从而导致基因组突变水平增加，进而导致癌症可能性更高。这种机制的论证将是一个重大进步，因为它是新颖的，并且提出了治疗干预的多个要点。

 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.