SIV and CD4 depletion distinctly reactivate latent <i>Mycobacterium. tuberculosis</i> infection

Abstract Human immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB) regardless of CD4 T cell count. Using a well-characterized cynomolgus macaque model, we compared reactivation of latent M. tuberculosis (Mtb) infection induced by simian immunodeficiency virus (SIV) or anti-CD4 antibody (αCD4). Reactivation, as defined by the appearance of a new lung lesion by PET CT, occurred in 5 of 7 αCD4 treated animals compared to 4 of 8 SIV infected animals within 2 months of treatment. αCD4 animals had significantly fewer CD4 T cells within granulomas compared to SIV/Mtb infected animals. However, compared to αCD4 groups, SIV infection caused more dissemination of lung granulomas and higher granuloma bacterial burdens. Within the granulomas, SIV replication was associated with greater Mtb growth and reduced Mtb killing. Granulomas from SIV/Mtb animals displayed a distinctly different profile of T cell cytokine and granzyme B expression compared to αCD4 animals and controls. PET CT imaging prior to treatment could predict reactivation in αCD4-treated animals, but not in SIV/Mtb animals. These data suggest that SIV infection disrupts protective immune responses against Mtb infection beyond the loss of CD4 T cells, and that synergy between SIV and Mtb occurs within granulomas.