DESCRIPTION (applicant's abstract): An international research scientist development award will support James G. Kublin, MD, MPH to become an independent investigator in international health. Dr. Kublin is a research fellow at the University of Maryland, and is currently conducting field and laboratory research on drug resistant malaria in Malawi, Central Africa. Two recent studies found that trimethoprim-sulfamethoxazole (TS) prophylaxis benefited HlV-infected persons in Cote d'lvoire. TS shares its mechanism of action with pyrimethamine-sulfadoxine (PS) and other antifolate drugs used to treat malaria. Resistance to the antifolates in Plasmodium falciparum is caused by point mutations in dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). In vitro studies suggest that TS will select resistance-conferring DHFR and DHPS mutations in P. falciparum. Such selection could accelerate the development of Plasmodium falciparum resistance to antifolate antimalarials in areas where HIV infection and malaria are both highly prevalent. HlV-infected persons receiving TS prophylaxis who are or become infected with P. falciparum may be more likely to fail PS treatment and to progress to severe disease and death. Antifolate-resistant P. falciparum malaria is increasing in the same African countries where HIV infection rates are highest, including Malawi. Bacterial pathogens prevented by TS prophylaxis appear to be less susceptible to TS in Malawi than in the Cote D'lvoire studies. The potential impact of TS prophylaxis on antifolate-resistant malaria needs to be assessed quickly and definitively, and the benefit of TS prophylaxis demonstrated thus far in a single setting needs to be confirmed in settings with high malaria endemicity and different bacterial resistance profiles. The overall research aims of this project are to determine whether the benefits of TS prophylaxis seen in Cote d'lvoire can be confirmed in Malawi, and to test the hypothesis that TS prophylaxis selects for antifolate- resistant P. falciparum and is associated with higher rates of PS treatment failure. This will be accomplished in a prospective, double-blinded, placebo-controlled trial in an area of Malawi with high rates of both HIV and malaria. Dr. Kublin will continue his training at the Center for Vaccine Development in Baltimore, Maryland and at the Malaria Project in Blantyre, Malawi. Dr. Christopher V. Plowe and Pr. Malcolm E. Molyneux, noted specialists in malaria research, will be his mentors throughout the training period. At the end of the training period Dr. Kublin will be well-positioned to develop an independent research program in international health.