HIV and malaria are two of the most important infectious diseases in the world, and both inflict the greatest harm in sub-Saharan Africa. Interactions between these two illnesses are of tremendous public health importance. The greatest burden of malaria is in children, yet surprisingly, the effect of HIV on the incidence of malaria in this population is poorly understood. In both children and adults, the effect of HIV on malaria treatment outcomes is poorly characterized, and the introduction of trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis for HIV disease raises the possibility that cross-resistance may jeopardize response to first-line malaria treatments. Conversely, little information is available on the impact of malaria on the progression of HIV disease. We propose to investigate the epidemiology of HIV and malaria co-infection through a series of studies in Kampala, Uganda. These studies will be conducted at a time of rapid expansion of antiretroviral (ARV) therapy in Uganda, both allowing us to study the effects of ARV therapy on malaria/HIV co-infection, and ensuring that our findings will be relevant for future HIV care in sub-Saharan Africa. Our aims will be: 1) To determine if HIV-infected children are at increased risk for symptomatic malaria. We will test the hypothesis that HIV infection is associated with an increased incidence of symptomatic malaria among children in Kampala. Secondary aims will be to evaluate the effects of the level of immunosuppression, TMP/SMX prophylaxis, and the use of ARV therapy on malaria incidence. 2) To assess the effect of malaria on the progression of HIV disease. Using a cohort of 300 HIV-infected children, we will test the hypothesis that symptomatic malaria is associated with accelerated progression of HIV disease, as measured by change in CD4 cell count and progression to AIDS and death. 3) To compare the response to therapy for uncomplicated malaria in HIV-infected and uninfected children and adults. We will test the hypothesis that HIV infection is associated with a higher risk of treatment failure following therapy for uncomplicated malaria. 4) To assess the effect of TMP/SMX prophylaxis on the selection of drug-resistant malaria parasites. We will test the hypothesis that the use of TMP/SMX prophylaxis is associated with an increased risk of infection with malaria parasites containing mutations that confer resistance to antifolate anti-malarials. This proposal builds on an established collaboration between UCSF and Makerere University. A major focus of this project will be continued capacity building and technology transfer to Uganda. Specifically, we will establish a research infrastructure to implement comprehensive longitudinal studies in well defined cohorts, create an onsite data collection center, establish a molecular malaria laboratory, and foster training for independent research in Uganda. The work will be performed principally in Uganda, with Ugandans playing major roles. Our long-term goals are to develop effective and sustainable research capabilities in Uganda, to promote the establishment of improved clinical management strategies, and ultimately to improve local and international standards of care for HIV and malaria.