Cellulose acetate phthalate (CAP) has been used as an enteric film coating material or as a matrix binder for tablets and capsules. It is widely used in oral pharmaceutical products and is generally regarded as a nontoxic material free of adverse effects. It is included in the FDA Inactive Ingredients Guide and is listed in pharmacopoeias internationally. CAP is available in large quantities and is inexpensive. It was demonstrated that CAP: 1) has antiviral activity against HIV-1 and several herpesviruses (HSV); and 2) when formulated in a micronized form a) inactivated in vitro HIV-1, HSV-1. HSV-2, cytomegalovirus, Neisseria gonorrhoeae, Trichomonas vaginalis, Haemophilus ducreyi and Chlamydia trachomatis; b) inactivated bacteria associated with bacterial vaginosis; c) protected mice against vaginal infection by HSV-2; and d) protected 4/6 rhesus monkeys from vaginal infection with simian immunodeficiency virus (SIVmac251). These results have established the promise of CAP as a microbicide for prevention of sexual transmission of HIV-1. Additional preclinical studies are needed to further support this promise. This includes: (Project I): Prevention of infection by primary HIV-1 isolates and distinct HIV-1 clades in cell cultures in vitro and in human cervical and rectal tissue models; (Project II): a) Assess the safety of CAP in a monkey model by colposcopic examinations and measurement of pro-inflammatory chemokines and cytokines; b) Assessment of CAP distribution after vaginal application in monkeys using chemically tagged CAP and colposcopy, and magnetic resonance imaging (MRI); and c) Evaluate the efficacy of CAP against infection with pathogenic X4- and R5-specific simian/human chimeric HIV viruses (SHIV), respectively; (Project III): Measurement of pro-inflammatory chemokines and cytokines after exposure of cervical and vaginal epithelial cells in culture to CAP; (Project IV): Studies on CAP-human sperm interactions to assess the spermicidal/contraceptive potential of CAP and its formulations. Information gained from the proposed studies, coordinated and supplied by uniform and quality controlled formulations by Cores A, B, respectively, is expected to facilitate the design of Phase I, II and III human clinical trials. CAP meets criteria proposed for an ideal microbicide: activity in presence of semen and blood; activity against sexually transmitted infections other than HIV-1; condom compatibility, negligible systemic absorption (due to its large, molecular mass and micronized state); lack of color and unpleasant taste; and low cost. The proposed research is expected to help transform this ideal into a reality.