Human immunodeficiency virus (HIV) transmission through saliva is extremely low. Several oral components, including secretory immunoglobulin A and secretory leukocyte protease inhibitor, are known as potential inhibitory agents of HIV oral transmission. Here we examined anti-HIV activity of oral bacterial components. We showed that recombinant protein HGP44 derived from Porphyromonas gingivalis, one of the primary infectious agents of periodontitis, was capable of inhibiting HIV type 1 (HIV-1) replication. HGP44 bound specifically to HIV-1 gp120 and blocked HIV-1 envelope-mediated membrane fusion. These findings suggest that HGP44 of P. gingivalis can inhibit HIV-1 infection by blocking HIV-1 entry.The predominant mode of human immunodeficiency virus (HIV) transmission is by sexual contact through broken mucosal or epidermal epithelia. It is rather clear that oral transmission of HIV is a rare event relative to vaginal and rectal transmission (3,32). It has been reported that fewer infectious HIV particles are in saliva than in other body fluids, such as blood, semen, and vaginal and cervical secretions (25). However, hyperexcretion of HIV type 1 (HIV-1) RNA in saliva has been reported previously (27). It appears that 87% of HIVinfected patients had plasma titers exceeding those in saliva, and 7% of the 67 tested individuals had a fourfold or higher viral load in saliva relative to that than in plasma (27).Several endogenous oral components are proposed to contribute to inactivating HIV, either alone or in combination (28). Among them, the secretory leukocyte protease inhibitor has been extensively studied. The secretory leukocyte protease inhibitor was first described by Thompson and Ohlsson (30) as a potent inhibitor of leukocyte elastase. Since then, studies from many independent laboratories have confirmed its anti-HIV-1 activity in in vitro assays (17,19,28). Recently, a novel mechanism of anti-HIV activity has been proposed; this mechanism involves the unique hypotonicity of saliva (2, 3). The tonicity of saliva is approximately 14% of that of blood and other mucosal secretions. Peripheral blood mononuclear cells were rapidly disrupted in saliva in an in vitro study. The hypothesis is that cell-associated HIV is released due to saliva disruption, and cell-free HIV is mostly neutralized by a specific antibody or inhibited by other macromolecular inhibitors in saliva.Despite the great effort that has been made to search for oral inhibitors of HIV, little information is available on the interaction of HIV and bacteria in the oral cavity, an environment harboring over 30 genera representing more than 500 species of bacteria (21). We speculated that oral bacteria may contain anti-HIV activity and create a microenvironment unfavorable for HIV infection. In this study, members of a group of oral bacteria were examined for their abilities to inhibit HIV-1. We demonstrated that Porphyromonas gingivalis, an organism frequently detected in the mouths of adult periodontitis patients, produced an antiviral molecule(s)...