Human Immunodeficiency Virus type-1 (HIV) and Mycobacterium tuberculosis (Mtb) are among the leading causes of death worldwide with coinfection associated with increased mortality and greater likelihood of selection for Mtb multi-drug resistance. Treatment of Mtb in the presence of HIV/AIDS is complicated by the immunosuppression associated with HIV infection and the pharmacologic interactions between drugs used for treatment of both pathogens. New approaches for treatment are needed that can inhibit Mtb, permit treatment of HIV without complex drug-drug interactions and are affordable in developing countries. Mtb is an intracellular pathogen that persists within macrophage phagosomes through interference with phagolysosome biogenesis. Increasing evidence suggests that the induction of autophagy promotes the maturation of phagosomes containing Mtb that suppress mycobacterial survival. Recently, we have discovered that HIV infection of macrophages, similar to Mtb, inhibits autophagy, while induction of autophagy inhibits HIV replication. Of note, our preliminary data suggest that calcitriol the active form of vitamin D3, long associated with possible activity against Mtb, also promotes autophagy and the antimicrobial peptide cathelicidin both of which inhibit HIV infection. This R21 application is based on the premise that induction of autophagy and cathelicidin by vitamin D3 in persons coinfected with HIV and Mtb will augment standard treatment of both infections and improve outcome. The specific aims of this proposal are to: 1. Establish the ability of vitamin D3 (calcitriol) to improve Mtb killing and inhibit HIV infection in coinfected monocyte-derived-macrophages (MDM));and 2. Identify the mechanism(s) of vitamin D3 mediated inhibition of Mtb and HIV in coinfected macrophages. The laboratory experiments proposed will establish the scientific justification for a clinical study of calcitriol designed to treat persons coinfected with both pathogens. Additionally, this research will demonstrate the potential benefit of enhancing innate immunity to control microbial infections including Mtb/HIV coinfection. PUBLIC HEALTH RELEVANCE: 7. It is expected that the studies outlined in this grant will establish the ability of calcitriol (the active form of vitamin D3) to induce autophagy and the antimicrobial peptide cathelicidin sufficiently to promote intracellular killing of HIV and Mycobacterium tuberculosis.