HIV-1 infection is associated with the development of acquired immunodeficiency syndrome (AIDS), a devastating disease affecting over 40 million people worldwide. Oral transmission of HIV appears to be a rare event, compared to a much higher risk of vaginal and rectal transmission. In search for the explanations for this phenomenon, intensive studies have focused on identification of oral components that are responsible for inhibition of HIV oral transmission. In our ongoing studies, we have demonstrated that Porphyromonas gingivalis, a periodontopathogen detected in most disease sites of periodontitis patients, possesses the ability to inhibit HIV induced membrane fusion. Our long-range goal is to fully understand the involvement of oral bacteria in the oral transmission of HIV and to provide the basis for development of effective anti-HIV therapies. The hypothesis for this proposal is that P. gingivalis is a potent oral inhibitor of HIV transmission, and that the primary mechanism of the inhibition is that a P. gingivalis component specifically interferes with one of the key steps in the early stage of HIV infection. To test the hypothesis, we will start with identification and purification of the inhibitory molecule. The inhibitory molecule will be characterized in the term of functional and genetic structures. We will also attempt to elucidate the molecular target of the P. gingivalis inhibitory component. Experiments are designed to examine every possible event where the bacterium steps in and leads to an aborted viral entry. Special effort will also be made to evaluate the clinical potential of the inhibitory molecule by determining its anti-viral spectra. Finally, studies will be initiated to investigate the effect of co-infection of HIV and P. gingivalis on the pathogenicites of the organisms. The successful completion of the proposal will be a significant advance in the understanding of the role of P. gingivalis in HIV oral transmission. Furthermore, the study of P. gingivalis inhibitory protein may lead to a discovery of an additional target to complement the current anti-HIV targets which are either reverse transcriptase or protease.