HIV induced anti-cancer HERV immunity in prostate, breast and colon cancers

 描述(由申请人提供)：这份新的R01申请是对RFA-CA-15-012“潜在艾滋病毒感染的癌症中的挑衅性问题(R01)”的回应，并回应了PQ6：“为什么艾滋病毒感染者中只有某些癌症类型增加，而其他癌症类型没有变化，甚至减少”？在过去的十年里，我们小组发表了关于艾滋病毒感染对人类内源性逆转录病毒(HERV)表达的影响的文章。我们关注的是人类基因组中最新的HERV，HML-2，缩写为HK2。我们的数据表明，在HIV感染的细胞中，HK2被转录和产物被翻译，这依赖于HIV Vif。针对HK2产生的CTL在体外可清除HIV感染的细胞。此外，我们还发现精英管制员具有更高的HK2特异性CTL和抗体反应频率。这表明，在感染艾滋病毒的患者中，抗HK2免疫反应可能是免疫监测系统的一部分，以控制病毒血症。在人类癌症中，HERV被怀疑参与了一些癌症的发生，在生殖细胞肿瘤、前列腺癌和乳腺癌、黑色素瘤、肾癌中检测到了HERV的表达。然而，HK2在癌症过程中的RNA、蛋白质和颗粒的表达并不能确定HK2活性在人类癌症病因学中的作用。在艾滋病毒感染中，许多癌症的发病率没有增加，甚至有所下降，如乳腺癌、前列腺癌或结肠癌。我们最近开发了一种新的计算途径程序“telescope”，它可以使用RNAseq数据集来精确定位HERV转录在染色体上的位置。在初步研究中，我们使用这一途径定位了HERV在HIV感染细胞中的表达，并发现了HERV表达的独特染色体模式。我们假设HIV重新激活HERV可以刺激抗HERV免疫，这种免疫特异性识别HERV也在前列腺癌、结肠癌和乳腺癌中表达，并且这些HIV诱导针对在乳腺癌、结肠癌或前列腺癌中表达的HERV的HERV特异性免疫反应。我们提出了三个目标：目标1：利用计算途径程序“望远镜”从公开来源询问RNAseq数据，确定哪些HERV在前列腺癌、乳腺癌和结肠癌中表达，无论患者是否感染艾滋病毒。目的2：从美国国立卫生研究院资助的ACSR中存在的材料中，确定哪些HERV在前列腺癌、乳腺癌和结肠癌中表达，以及在有或没有HIV感染的患者中表达。目的：探讨前列腺癌、乳腺癌和结肠癌患者、HIV感染者和非HIV感染者的抗-HERV免疫应答。在这项提案中，我们的目标是开发和测试源自我们的初步数据的假设，这些假设将验证和扩大在存在或不存在HIV感染的情况下前列腺癌、结肠癌和乳腺癌中HERV表达的知识，并将特定的HERV表达和特定的抗HERV免疫与癌症免疫监测联系起来。

 DESCRIPTION (provided by applicant): This new R01 application is in response to the RFA-CA-15-012 "Provocative Questions in Cancer with an Underlying HIV Infection (R01)", and responds to PQ6: "Why are only certain cancer types increased whereas others are unchanged or even decreased in people with HIV infection"? Over the past decade our group has published on the effect of HIV infection on the expression of human endogenous retroviruses (HERVs). We have focused on the most recent HERV in the human genome, HML-2, abbreviated to HK2. Our data shows that in an HIV infected cell, HK2 is transcribed and products are translated, and that this is dependent on HIV Vif. CTL generated against HK2 can eliminate HIV infected cells in vitro. Furthermore, we have found that elite controllers have higher frequencies of HK2 specific CTL and antibody responses. This suggests that in patients with HIV infection, anti-HK2 immune responses could be part of the immunosurveillance system to keep viremia in check. In human cancers, HERVs have been suspected to be involved in pathogenesis of some cancers, with the detection of HERV expression in germ cell tumors, prostate and breast cancers, melanoma, renal cell carcinoma. However, HK2 RNA, protein, and particle expression during cancers does not ascribe a definitive role for HK2 activity in contributing to cancer etiology in humans. A number of cancers are not increased in incidence in HIV infection or are even decreased, such as breast, prostate or colon cancer. We have recently developed a novel computational pathway program, "telescope", which can use RNASeq data sets to pinpoint loci on a chromosome in which HERVs are transcribed. In preliminary studies, we have used this pathway to locate HERV expression in the context of an HIV infected cell, and find distinct chromosomal patterns of HERV expression. We hypothesize that HIV reactivation of HERV's stimulates anti-HERV immunity which specifically recognizes HERVs also expressed in prostate, colon and breast cancers, and that these HIV induced HERV specific immune responses which target HERVs which are expressed in breast, colon or prostate cancer. We are proposing three aims: Aim 1: To determine which HERVs are expressed in prostate, breast and colon cancers, in patients with or without HIV infection, using a computational pathway program "telescope" to interrogate RNASeq data from publically available sources. Aim 2: To determine which HERVs are expressed in prostate, breast and colon cancers, in patients with or without HIV infection from material existing within the NIH funded ACSR. Aim 3: To ascertain anti-HERV immune responses in patients with prostate, breast or colon cancers, in patients with or without HIV infection. In this proposal, we aim to develop and test hypotheses, stemming from our preliminary data, that will verify and expand the knowledge of HERV expression in prostate, colon and breast cancers in the presence or absence of HIV infection, and associate specific HERV expression and specific anti-HERV immunity with cancer immunosurveillance.