Effect of ART on 3D Oral Epithelium & KSHV/RRV Infection

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DESCRIPTION (provided by applicant): With the advent of highly active antiretroviral therapy (HAART) HIV/AIDS has become a manageable condition. Oral manifestations are often the earliest and most important indicator of HIV infections. HAART has significantly reduced some AIDS-related oral maladies. However, oral Kaposi's sarcoma (KS), one of the commonest oral complications of HIV infection, has reported little change with HAART use. Presently, nothing is known of the effect of antiretroviral therapy (ART) on the biology of oral KS. We hypothesize that in vitro three-dimensional oral epithelial models can be developed to study oral KS pathology, molecular biology, and investigate the effects of ART on oral KS. Using the exploratory/development R21 mechanism we are proposing to develop in vitro three-dimensional oral epithelial models for the study of KSHV (the etiological agent of KS) infection and replication. In our first specific aim we propose to use this model to investigate the effect of ART on the life cycle of KSHV in oral epithelium. Three different oral models will be used consisting of tonsil, buccal, and gingival epithelium. These models will support investigations on the mechanisms of the virus-host interactions that control the expression profiles and importantly how a specific ART or a category of ART is impinging on the molecular biology of the KSHV life cycle. They will also provide a platform on which new antiretroviral therapies can be tested for adverse effects. Primate models are excellent models for the study of AIDS and AIDS-associated infections, however the cost of using primates is inhibiting. We hypothesize that organotypic raft cultures of primate oral epithelium can provide a relatively simple and less expensive system using a physiologically relevant tissue model to complement and focus primate studies. In our second specific aim we propose to develop three-dimensional primate oral epithelial models to study the effect of ART on their growth and differentiation. Rhadinovirus (RRV) is the primate homolog of KSHV. Similar to KSHV in human tissues we will investigate the effect of ART on RRV infection and replication in oral primate epithelium. Our in vitro primate tissue models will be important new tools for the study of HIV-associated oral diseases and ART induced effects on the oral cavity. Because oral KS in the HIV/AIDS population is still a clinically important problem and effects quality of life there is a continuous need to use antiretroviral therapies to manage the HIV infected population. As more and more patients take ART for longer period of times understanding the effect of ART of KS increases in importance. Our studies in this application and future studies evolving from them will have a significant impact on health care.