PROJECT SUMMARY Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) is the most common cause of mortality in HIV+ individuals. Although antiretroviral and antimycobacterial drugs have reduced the burden of TB in the HIV+ population, they are incompletely effective against this global health burden. The only available TB vaccine is the live attenuated mycobacterium Bacillus Calmette-Guerin (BCG) that is given intradermally to infants. While this provides substantial protection against non-pulmonary TB in childhood, it has little impact on pulmonary TB rates in adults. However, we have shown recently that BCG delivered intravenously (BCG IV) conferred dramatic protection from TB in SIV-negative macaques. Dr. Scanga conducted a preliminary study of BCG IV in his macaque model of HIV/Mtb co-infection. Animals infected with pathogenic SIV for several months that were then co-infected with virulent Mtb exhibited more severe TB than did similarly-infected SIV-naïve animals. In their preliminary study, vaccination of SIV+ macaques with BCG IV induced immunity that parallels that seen in SIV-naïve rhesus and conferred dramatic protection from TB in 6/7 animals. Furthermore, there were no signs of disseminated BCG. This unprecedented protection from TB in SIV+ animals provides exciting evidence that BCG IV can be safe, immunogenic, and protective in NHP with chronic SIV infection While these data are provocative, there is still much to learn about the mechanisms by which BCG IV provides such striking protection. In this R01 proposal, we will extend these exciting results to refine the ability of BCG IV to protect SIV+ macaques from infection with Mtb. Most importantly, we will use comprehensive immunologic approaches, both biased and unbiased, to determine the immune correlates and mechanisms of BCG IV-mediated protection against TB in the context of pre-existing SIV. This will demonstrate that it may indeed be possible to protect persons infected with HIV from TB and will guide the development of TB vaccine approaches that can protect this highly vulnerable population. The team we have assembled includes experts in the field of TB, vaccines, and the cutting-edge technologies that will allow us to understand better the remarkable protection of SIV+ animals with BCG IV. We already have an established collaborative relationship and ensures successful completion of this very exciting study.