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.
We hypothesize that HIV reactivation of HERVs 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 target HERVs which are expressed in breast, colon or prostate cancer.