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.PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) infections are among the leading causes of morbidity and mortality among adult populations in the United States and globally. When HIV-positive individuals are co-infected with Mycobacterium tuberculosis, they are more likely to develop active TB disease and are at increased risk of dying from the infection. The reasons for this increased risk are not well understood. The studies proposed in this application address this issue. Understanding the mechanisms underlying the increased risk of TB in co-infected individuals is critical for developing a comprehensive understanding of the HIV/TB epidemic and may lead to new strategies to prevent TB in this high risk population. The proposed research is highly relevant to the mission of NIAID by addressing key questions in the prevention, management, and treatment of TB in HIV-infected individuals, and uses an innovative combination of field- and laboratory-based approaches to achieve the following aims: 1) Study the impact of HIV on the modulation of the innate immune response in TB disease, including mycobacteria-specific immunity and type 1 interferon production; 2) Determine the impact of HIV on the risk of TB disease in co-infected individuals; 3) Determine the impact of HIV on the incidence and severity of TB disease in co-infected individuals; and 4) Develop improved diagnostics to inform TB management in HIV-positive individuals, including tuberculosis infection, TB disease, and relapse. FILED