Pathology and mechanisms of increased M.tb growth and dissemination during co-infection with HIV-1

Around one third of the world’s population is latently infected with Mycobacterium tuberculosis (M.tb). M.tb and HIV have a deadly synergy that occurs during co-infection. Individuals with HIV infection are at significantly increased risk for acquiring or reactivating latent TB infections. Further, there is increased TB pathology and bacterial growth associated with co-infection with HIV. TB is the leading cause of death in people who are living with HIV. Here we describe the development of the first animal model of TB/HIV co-infection using the human pathogens themselves. We have demonstrated increased pathology and bacterial growth previously seen during co- infection in humans. We have also demonstrated increased neutrophil infiltration during HIV infection, which has been shown to be associated with worsened disease during M.tb infection. Conversely to what has been hypothesized in association with immune failure, during early co-infection, we have shown a significant increase in pro-inflammatory cytokines in the lung. We have further explored some of the potential mechanisms behind the increased bacterial growth seen during co-infection. We have seen that arginase levels in the lung are highly and significantly correlated with pulmonary bacterial growth. However, the basis of this association is yet to be determined. We have also begun the adaption of our humanized mouse model for the study of neuroAIDS and the impact of M.tb on HIV in the brain. This work provides an important framework for future translational studies into co-infection pathology and mechanisms.