Abstract: In recent years, AIDS-related mortality has dramatically decreased due to the highly active antiretroviral therapy (HAART) but the mortality caused by the non-AIDS-defining cancers, especially lung cancer (LC) is continuously rising. In the U.S., LC becomes the most common and most deadly non-AIDS- defining cancer in HIV(+) populations. Although smoking is a key risk factor for HIV associated LCs, HIV(+) individuals still have a significantly increased LC risk after controlling for smoking status, indicating that other factors are responsible for the higher LC incidence in HIV(+) populations. Existing etiology studies have been largely focused on the involvement of human papillomavirus (HPV) in non-HIV associated LCs. A study to investigate the role of HPV in HIV associated LCs has not yet been reported. To date, the view on whether or not HPV is associated with LCs is highly controversial, since the observed HPV infection rate in LCs varies from 0 to 100%. Further, the hypothetic role of HPV in LCs is mainly based on the detection of HPV genomic DNA in LCs. So far, none of the association studies has demonstrated that the detected HPV DNA is transcriptionally active in the lung tumor tissues. Without evidence of viral transcription, the causal role of HPV in LCs is highly questionable, since it's well known that HPV must be transcriptionally active in order to induce its associated cancers. The overarching goal of this proposal is to resolve this long-standing controversy of the involvement of HPV in LCs using our cutting-edge sequencing and informatics approaches and information obtained from the natural in vivo tumor environment. To accomplish this goal, we will first examine our hypothesis that HPV is causally associated with a subset of LCs in HIV(+) population, but not in the general population. The rest of the work will test our hypothesis that HPV promotes lung oncogenesis by inducing a unique set of cancer driver mutations and manipulating cancer pathways through synergistic expression of viral E5 and E7 genes. By conducting the proposed work, we expect to get solid evidence supporting a causal role of HPV in HIV associated LCs and obtain much needed, unprecedented insight into the unique mechanism underlying the HPV(+) LCs in HIV infected individuals, which may be particularly significant for future patient care and disease management.