UNAIDS estimates that 14,000 new HIV-1 infections occur every day despite widespread knowledge of the protective effects of abstinence and condom use. There are no vaccine candidates or topical microbicides that are known to protect humans from HIV-1 infection. Hence, novel approaches to HIV prevention warrant urgent evaluation. Recognizing this situation, the National Institutes of Health and the Bill and Melinda Gates Foundation are sponsoring a randomized clinical trial of the safety and effectiveness of daily oral tenofovir versus placebo in Cambodia. Tenofovir is a potent inhibitor of HIV-1 replication that is licensed for treatment of AIDS and has prophylactic effects in animal models. The clinical trial in progress will evaluate whether chemoprophylaxis with tenofovir reduces that rate of seroconversion during the period of treatment. The same group of investigators now proposes to extend this work to test the hypothesis that daily oral tenofovir may have durable benefits (or risks), compared with placebo, that extend beyond the period of chemoprophylactic treatment, including attenuation of the course of infection among those who become infected despite chemoprophylaxis (aim 1) due to preservation of immune responses (aim 2a) from prolonged viral antigen exposure (aim 3a). The durability of these benefits will be assessed during longitudinal follow-up. Those who remain seronegative despite viral exposure during chemoprophylaxis may develop HIV-specific immune responses (aim 2b) due to viral exposure that is contained by the antiviral drug (aim 3b). Seronegative individuals previously exposed to chemoprophylaxis may become partially resistant to HIV-1 infection due to the measured immune responses, or other factors, that will decrease seroincidence or attenuate the course of infection if seroconversion occurs (aim 4). We will also determine whether drug resistant infections occur more commonly during and after chemoprophylaxis exposure, and whether the drug resistant viruses remain predominate over time even after chemoprophylaxis is stopped, which has implications for secondary transmission. The proposed prospective cohort of seroconverting and seronegative women who have completed the randomized trial of tenofovir versus placebo are uniquely valuable. The evaluation of post-chemoprophylactic benefits and risks bears directly on the utility of this novel approach to HIV-1 prevention. Even if tenofovir chemoprophylaxis is found to be ineffective in preventing seroconversion, the proposed cohort will provide uniquely valuable insights into how extremely early suppression of viral replication with antiviral agents may influence viral-host interactions that govern HIV-1 disease progression.