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

 描述(申请人提供)：与普通人群相比，HIV-1感染患者中几种癌症的发病率更高。人们对这些观测的机制基础知之甚少。这份R21提案解决了RFA-CA-15-013，特别是具有挑衅性的问题2：“除了免疫功能障碍(包括炎症)，艾滋病毒介导的机制是导致HIV感染者不同癌症风险的基础？”我们将使用分子病毒学和分子生物学方法，结合生物信息学，研究病毒感染CD4阳性T淋巴细胞和信号机制之间的机制联系，该信号机制导致旁观者细胞中抗病毒APOBEC3酶的反式上调，导致基因组突变水平增加，进而导致更高的癌症可能性。这种机制的演示将是一个重大的进步，因为它是新颖的，并为治疗干预提供了多个方面的建议。

 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.