DESCRIPTION (provided by applicant): Oropharyngeal candidiasis (OPC) is the most common oral manifestation of HIV infection. The causative agent, Candida albicans, is both an opportunistic pathogen and common normal flora of the oral mucosa. Th1- type CD4+ cell-mediated immunity is considered the predominant host defense mechanism against OPC. However, this host response is negligible and irrelevant in HIV patients with reduced CD4+ T cell numbers. Instead other secondary host defenses against C. albicans are required under reduced CD4+ T cell conditions. The elucidation of oral anti-Candida immune defense mechanisms that can effectively operate in the absence of adequate numbers of CD4+ T cells is crucial for the development of novel immunotherapies that will enhance protective immune responses to OPC in HIV+ individuals. Accordingly, our studies have implicated CD8+ T cells as playing a putative 'secondary' role in host defense against OPC. In this role, CD8+ effector T cells are recruited into the oral mucosa and migrate throughout the lamina propria and epithelium, providing effector function where necessary. In OPC, however, they accumulate at the basolateral epithelial/lamina propria interface and correlates with a reduction in epithelial expression of the adhesion molecule, E-cadherin, which facilitates migration of CD8+ T cells in the epithelium. We hypothesize that CD8+ T cells have anti- Candida activity in the oral cavity, but optimal effector function is often precluded by Candida-mediated aberrations of tissue E-cadherin that can be reversed/restored therapeutically. Hence this project will focus on the uncharacterized anti-Candida host defense mechanisms by CD8+ T cells in the oral cavity, that we believe may be a novel immune mechanism and influenced by both the organism and components of antiretroviral or immuno therapies. Following completion of the project we expect to demonstrate how these 'secondary' type of immune responses function against Candida in the oral cavity, how and why they can be ineffective, and how existing antiretroviral and immune therapies not only link to these 'secondary' responses, but also how they can be exploited further to control OPC in HIV disease.

Oropharyngeal candidiasis (OPC), caused by the fungus Candida albicans, is an opportunistic infectious disease that afflicts up to 90% of HIV-infected persons as they progress to AIDS. Hence, this infectious disease is a major public health problem. The research proposed in this application will identify the mechanisms associated with host susceptibility to OPC with the long- term goal of developing immunotherapeutic strategies to reduce or eliminate symptomatic infections.