Antiretroviral therapy timing impacts latent tuberculosis infection reactivation in a tuberculosis/simian immunodeficiency virus coinfection model.

Studies using the nonhuman primate model of M. tuberculosis /Simian Immunodeficiency Virus co-infection have revealed protective CD4+ T cell-independent immune responses that suppress LTBI reactivation. In particular, chronic immune activation rather than the mere depletion of CD4+ T cells correlates with reactivation due to SIV co-infection. Here, we administered cART at 2 weeks post-SIV co-infection to study if restoration of CD4+ T cell immunity occurred more broadly, and if this prevented reactivation of LTBI compared to cART initiated at 4 weeks post-SIV. Earlier initiation of cART enhanced survival, led to better control of viral replication and reduced immune activation in the periphery and lung vasculature thereby reducing the rate of SIV-induced reactivation. We observed robust CD8+ T effector memory responses and significantly reduced macrophage turnover in the lung tissue. However, skewed CD4+ T effector memory responses persisted and new TB lesions formed post SIV co-infection. Thus, reactivation of LTBI is governed by very early events of SIV infection. Timing of cART is critical in mitigating chronic immune activation. The novelty of these findings mainly relates to the development of a robust animal model of human Mtb/HIV co-infection that allows the testing of underlying mechanisms.