Summary/Abstract In the era of potent antiretroviral therapy (ART), the rates of new HIV-1 infection and AIDS-associated death have declined worldwide. Nonetheless, an estimated total of 1.8 million people became newly infected in 2017. Current ART fails to clear the virus, and thus life-long adherence to treatment is necessary for individuals living with HIV-1. Prevention is essential to stop this global epidemic, but no prophylactic vaccines or microbicides are currently available. A better understanding of key determinants influencing HIV-1 transmission is needed for developing innovative, efficacious strategies to prevent HIV-1 acquisition. The most common route of HIV-1 transmission is via sexual contact, especially during penile-vaginal and penile-anal intercourse. Many biologic factors that increase the probability of sexual HIV-1 transmission have been studied, including microbial perturbation associated with bacterial vaginosis and with sexually transmitted diseases caused by viruses and bacteria. The reason for this enhanced transmission is commonly thought to be increased inflammation and recruitment of activated, highly permissive target cells to the mucosal sites in the donor or the recipient. However, little is known about the biologic consequences of HIV-1 interaction with bacteria. Our preliminary study demonstrated that HIV-1 can bind to E. coli via the interaction of HIV-1 envelope (Env) N-glycans with FimH, a mannose-specific lectin expressed on the fimbria of uropathogenic E. coli that can colonize the genitourinary tract and cause urinary tract infection. Importantly, unlike the antiviral properties of other lectins with binding affinity for Env, FimH interaction does not interfere with and may even enhance HIV-1 infectivity. Based on these data, we propose a novel hypothesis that a direct interaction between HIV-1 and certain bacteria present in the genitourinary mucosa promotes virus infectivity and transmissibility. To test this hypothesis, we will first perform in vitro experiments to examine the interaction of HIV-1 Env from major clades, especially Env of transmitter/founder strains, with FimH protein and FimH-bearing E. coli, and then we will assess how such an interaction affects virus stability and transmissibility to target cells (Aim 1). Subsequently, we will use a humanized mouse model to determine whether mucosal exposure to HIV-1 in conjunction with FimH-bearing E. coli enhances the likelihood for HIV-1 acquisition (Aim 2). As a result of the proposed study, we expect to gain a better understanding of the importance of direct HIV-1 interaction with bacteria in determining the efficiency of mucosal transmission of HIV-1. These data will provide valuable insights into and clinically practical leads toward new approaches to decreasing the risk of HIV-1 sexual transmission.