HIV co-infection is the most critical risk factor for the reactivation of latent tuberculosis (TB) infection (LTBI). While CD4⁺ T cell depletion has been considered the major cause of HIV-induced reactivation of LTBI, recent work in macaques co-infected with Mycobacterium tuberculosis (Mtb)/simian immunodeficiency virus (SIV) suggests that cytopathic effects of SIV resulting in chronic immune activation and dysregulation of T cell homeostasis correlate with reactivation of LTBI. This review builds on compelling data that the reactivation of LTBI during HIV co-infection is likely to be driven by the events of HIV replication and therefore highlights the need to have optimum translational interventions directed at reactivation due to co-infection.