Pre-existing SIV infection decreases cytokine responses by T cells in lung during the early stages of M. tuberculosis co-infection

Abstract

Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death among HIV+ individuals. The precise mechanisms by which HIV impairs the immune response to subsequent Mtb infection are unknown. We previously established a model of co-infection in Mauritian cynomolgus macaques (MCM). We found SIV/Mtb co-infected MCM had rapidly progressive TB and reached humane endpoint by 12 weeks post-Mtb infection. We hypothesized that pre-existing SIV impacts T cell responses at the early stages of Mtb infection. We infected MCM with SIVmac239 intrarectally and 6 months later co-infected with a low dose of Mtb. SIV-naïve MCM were infected with Mtb alone as controls. Animals were monitored by clinical parameters, culturing bacilli in gastric and bronchoalveolar lavages, and serial 18F-FDG PET/CT imaging. Six weeks after Mtb infection, animals were necropsied and immune responses in the lung were measured by flow cytometry. The two groups exhibited similar TB disease at time of necropsy. Total bacterial burden was remarkably high in both SIV-naïve and SIV/Mtb groups, although co-infected animals tended to have more bacteria in lung tissue. At sites of Mtb infection, SIV/Mtb co-infected animals had fewer CD4+ T cells and significantly more CD8+ T cells. TNFα production by these CD4+ and CD8+ T cells was decreased. Taken together, pre-existing SIV decreases the quality of cytokine responses by T cell at sites of Mtb infection during the early stages of TB disease. This appears to be a critical time point at which the immunologic defect from pre-existing SIV infection begins to impact the arc of TB disease.