SUMMARY The overall incidence of HPV+ head and neck squamous cell carcinoma (HNSCC) has exhibited an increasing trend over the last few decades, and has now in the U.S. overtaken cervical cancer as the most common site of HPV related cancer. The majority of patients present with advanced-stage HNSCC are without a clinical history of pre-malignancy. Because there is a paucity of pre-cancer clinical samples the studying the steps of cancer progression that would provide an understanding of the carcinogenic we have developed an in vitro progression model. Interestingly, HPV+ patients compared to HPV negative (HPV-) patients have an improved overall prognosis and greater disease-free survival, attributed partly to a better response to radio- and/or chemotherapy. The mechanisms and natural history of oral HPV infection and carcinogenic progression are poorly understood. Men and women infected with human immunodeficiency virus (HIV) have higher rates of HPV16 infection, longer persistence of HPV16, increased incidence of HNSCC, poorer prognosis, as well as more recurrences after definitive therapy. There have been substantial changes in the burden of cancer affecting HIV-infected individuals in the U.S. during the period spanning the introduction of highly active anti- retroviral therapy (HAART). Scaling-up of HAART therapy has dramatically increased the life expectancy of people living with HIV (PLHIV). As a result of these temporal changes, non-AIDS-defining cancers have come to comprise the majority of cancers in HIV-infected persons during the HAART era. Among these emerging malignancies, HPV-associated cancers of the oral cavity/pharynx increased significantly following an AIDS diagnosis. Most patients with HIV/HPV co-infections on HAART therapy have reduced risk of developing HPV-associated cancers such as cervical cancer but have a higher risk of developing HPV-associated oral cancers the risk is suggested to be due to longer life expectancy as a results of HAART therapy. But it is unclear why HAART therapy may have different effects on HPV+ HNCSCC versus HPV+ cervical cancers. Our overarching hypothesis is that HAART therapy affects the progression of HPV+ HNC. This increases the numbers of PLHIV who have persistent oral HPV infections that progress to HNCSCC, poorer prognosis, and death. We propose to focus on three areas to test this hypothesis. Specific Aim 1. Analyze HAART induced differences of HPV carcinogenic propensity in oral epithelial cells. Specific Aim 2: Investigate the effect of HAART on carcinogenic markers and metabolic pathways associated with HPV+ HNSCC. Specific Aim 3: Study the effect of HAART on glycolysis versus mitochondrial respiration.