Tuberculosis (TB), a major public health problem worldwide, is undergoing a resurgence in the United States, largely as a result of TB reactivation in patients infected with the Human Immunodeficiency Virus-1 (HIV) New information is needed for development of novel TB control strategies. The clinical immunology studies described in this proposal are directed toward the long-range goal of gaining greater understanding of host defenses in TB. At the same time, the results of these studies should provide some new insights into the immunopathogenesis of AIDS. To assess the possibility that TB reactivation is due to the development of qualitative defects in certain immune responses in HIV+ patients, HIV- infected (HIV+) and uninfected (HIV-) subjects who have no TB (PPD-), latent TB (PPD+) or active TB will be compared for a variety of relevant clinical and immunological parameters including: quantitative T cell subsets; in vitro lymphoproliferative responses to Mycobacterium tuberculosis (Mtb) and unrelated antigens and lectin mitogens; production of selected cytokines (interferon-gamma, TNF, and other) in response to Mtb antigens; cell-mediated cytotoxicity to cells bearing Mtb antigens; and activation of intracellular cytostasis of Mtb. In addition, selected individuals from the HIV+/PPD+ group will be studied in a longitudinal manner to assess effects of TB reactivation on these parameters. Statistical analysis carried out during the course of these investigations will incorporate appropriate consideration of stratification and """"""""power"""""""". Subjects (primarily prisoners, intravenous drug users, Blacks, Hispanics, and women -- populations at particular risk for dual HIV-TB infection) will be recruited at a state hospital. Based on the results of these studies, future experiments are planned to predict the T cell epitopes of sequenced Mtb protein antigens and test subjects' lymphocyte responses to the corresponding synthetic peptides. These investigations may reveal selected qualitative defects associated with TB reactivation in HIV disease, shedding light on host defenses that maintain TB latency. The findings may eventually contribute to the design of an effective synthetic subunit vaccine against Mtb that could be used in immunocompromised hosts such as subjects with HIV infection.
