Human immunodeficiency virus (HIV) is a highly lethal lentivirus which over a protracted course destroys the host's adaptive immune system leaving them vulnerable to numerous opportunistic infections. Unlike most viruses whose genome replicates independently of the host cell's genome, the HIV-1 genome integrates into and is replicated with the host genetic material. Therefore, even if therapeutic approaches can inhibit new virus production, the viral genome remains intact and competent. Therefore, strategies that can prevent the uptake and integration of the virus would be of tremendous clinical value. The vast majority of HIV infections occur as a consequence of viral transmission through mucosal surfaces, such as the vaginal mucosa. The delivery of siRNAs that specifically silence host factors required for early events in the HIV life cycle to lymphocytes in the vaginal mucosa could prove to be an effective means of protecting individuals from HIV infection and serve as a potential microbicide. One of the main challenges facing the clinical application of siRNAs as a genetic therapy is the ability to delivery siRNAs to the cytoplasm of the appropriate target cell types. We have recently developed a novel lipid nanoparticle that is coated with an antibody recognizing the integrin molecule LFA-1 which is broadly expressed on lymphocytes. These immuno-nanoparticles will be used to deliver siRNAs to lymphocytes present in the vaginal mucosa of humanized mouse models of HIV. Given the high level of sequence heterogeneity, the propensity of HIV-1 to mutate and the inability of anti-HIV siRNAs to target the incoming viral RNA genome and prevent integration, alternative therapeutic targets are required to prevent the transmission of HIV. Host factors that are necessary for early events in the HIV lifecycle but are dispensable for cellular functioning could prove to be an effective therapeutic alternative. Using a high-throughput RNA interference-based screening platform, we have identified a large number of potential therapeutic targets that could serve to inhibit HIV integration when silenced. However, these factors require extensive analysis and characterization to ensure their safety and efficacy. We will be combining the LFA-1-mediated cell-type specific vehicle to introduce siRNAs targeting therapeutically relevant host factors as a potential means to inhibit viral infection in humanized mouse models of HIV. These experiments will provide the preclinical groundwork necessary for the development of an effective RNAi-based anti-HIV microbicide. Heterosexual transmission is the leading cause of new HIV infections in the world. A microbicide providing true intracellular immunity would make a significant contribution to controlling the spread of this deadly virus.