Use of highly active antiretroviral therapy (HAART) has made HIV/AIDS a manageable condition. Oral manifestations are often the earliest and most important indicator of HIV infections. Oral health is significantly linked to both physical and mental health improvement, and adverse oral health can lead to incomplete adherence to treatment regimens risking relapse in the patient and increasing the potential for development of drug resistance viruses. Use of HAART has resulted in a significant reduction in serious adverse oral conditions such as oral hairy leukoplakia, necrotizing ulcerative periodontitis, and oral candidiasis. Patients taking antiretroviral therapy (ART) have shown a significant increase in the development of HPV oral warts;particularly in patients presenting increased CD4 cell counts and reduced HIV load. We hypothesize that ART use is directly related to the increase of HPV oral lesions. To understand how ART is affecting the increase in oral lesions several important gaps in our knowledge need to be filled in. All of our studies will depend on using our three-dimensional organotypic raft culture system. Raft culture tissue has been to shown faithfully mimic its in vivo counterpart and represents a physiological relevant in vitro model. We have nearly 20 years experience using raft culture technology. Specific Aim 1 proposes to investigate the effect of ART on oral epithelial growth, differentiation, and wound healing. Adverse effects of ART on growth, differentiation, and wound healing would have a negative impact on oral health and provide mechanisms for observed changes in HPV infection and biology. Tonsil, buccal, and gingival epithelium will be studied. Specific Aim 2 proposes to study the replication of HPV in oral epithelium. Presently, it is not known if oral epithelium is permissive for replication of infectious HPV and what effect ART has on HPV permissive replication. If oral tissue is defective for permissive replication then Aim 2 is designed to define the nature of the defect in the viral life cycle. Productive oral lesions would make the oral cavity a site for the potential spread of HPV. In Aim 2 we will also investigate if ART is able to increase the infectivity of oral epithelial cells providing a mechanism for the increase in oral lesions seen in HIV/AIDS patients using HAART. Specific Aim 3 proposes to define the differentiation-dependent life cycle of HPV32 and HPV16 oral epithelium and test the effects of ART on their life cycles. Presently, nothing is known in any system about the life cycle of HPV32 and little is know about the life cycle of HPV16 in oral epithelial tissues. Our studies will provide an extensive map of the life cycles these two HPVs in oral epithelium and how ART impinges on their life cycles. We hypothesize that some of the effects of ART will be related to pathology of the infections, such as increases in HPV oncogenes E6 and E7 expression.