SUMMARY In recent years, the incidence of AIDS-defining cancers has dramatically decreased due to the HAART therapy. In contrast, the incidence of the non-AIDS-defining cancers (NADC), especially lung cancer (LC) has risen by more than 3 fold. In the U.S., LC has become the most common NADC with an incidence rate of 204 cases per 100,000 person-years. LC is also the most common NADC cause of death and accounts for 21% of cancer- related death in the HIV(+) population. Although smoking is a key risk factor for HIV associated LCs, HIV(+) individuals still have a 3-fold increased LC risk after controlling for smoking status, indicating that other factors are responsible for this increased incidence. Unlike other common HIV associated cancers such as cervical cancer, non-Hodgkin's lymphoma, and Kaposi's sarcoma, HIV associated LCs do not have a known viral etiology. To discover any potential oncopathogen for HIV associated LCs, we have utilized our Next- Generation-Sequencing-based PARSES pipeline to interrogate more than 1,000 LC RNA-seq data sets. We discovered that human papillomavirus (HPV) is causally associated with LCs in the HIV(+) population. The overarching goal of this proposal is to determine the involvement of HPV in HIV associated LCs using our well- established sequencing based informatics approaches as well as newly created HPV(+) HIV associated LC model systems. We will first examine the hypothesis that there is a causal association between HPV and LCs in the HIV(+) population but not in the general population. In addition, we will test the hypothesis that HPV promotes lung oncogenesis by enhancing the estrogen-mediated growth signaling and expressing viral E5/E6/E7/hpv-circ-880-408 oncogenes in the HIV(+) individuals. We will elucidate the critical roles of HPV oncogene products including a novel viral circular RNA and estrogen-mediated growth signaling and immune- evasion in HIV associated lung carcinogenesis. We will simultaneously examine an important concept of being able to precisely treat HPV(+) HIV associated LCs with anti-estrogen and/or anti-HPV regimens in the era of personalized medicine. Further, by determining the HPV etiology, our work may help prevent LCs by promoting HPV vaccination for both sexes. Together, completion of the research will add conceptually to our understanding of HIV associated LCs and provide potentially unique therapeutic opportunities and ultimately benefit a subset of HIV(+) LC patients.