Reactivation of Latent Tuberculosis in Cynomolgus Macaques Infected with SIV Is Associated with Early Peripheral T Cell Depletion and Not Virus Load

Abstract

HIV-infected individuals with latent Mycobacterium tuberculosis (Mtb) infection are at significantly greater risk of reactivation tuberculosis (TB) than HIV-negative individuals with latent TB, even while CD4 T cell numbers are well preserved. Factors underlying high rates of reactivation are poorly understood and investigative tools are limited. We used cynomolgus macaques with latent TB co-infected with SIVmac251 to develop the first animal model of reactivated TB in HIV-infected humans to better explore these factors. All latent animals developed reactivated TB following SIV infection, with a variable time to reactivation (up to 11 months post-SIV). Reactivation was independent of virus load but correlated with depletion of peripheral T cells during acute SIV infection. Animals experiencing reactivation early after SIV infection (<17 weeks) had fewer CD4 T cells in the periphery and airways than animals reactivating in later phases of SIV infection. Co-infected animals had fewer T cells in involved lungs than SIV-negative animals with active TB despite similar T cell numbers in draining lymph nodes. Granulomas from these animals demonstrated histopathologic characteristics consistent with a chronically active disease process. These results suggest initial T cell depletion may strongly influence outcomes of HIV-Mtb co-infection.

CD4 + T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

“…Macaques serve as excellent models of human Mtb/HIV coinfection because they can establish LTBI and are susceptible to simian immunodeficiency virus (SIV), providing a valuable surrogate model for pathogenic HIV infection (22)(23)(24)(25)(26). Coinfected macaques recapitulate key aspects of the human disease, including CD4 + T-cell depletion, reactivation of LTBI, and dissemination of the bacilli (22,25).…”

“…Coinfected macaques recapitulate key aspects of the human disease, including CD4 + T-cell depletion, reactivation of LTBI, and dissemination of the bacilli (22,25). As part of the current investigation, we sought to understand the dynamics of TB disease progression following high-dose SIV coinfection in rhesus macaques and to establish the correlates associated with reactivation of LTBI.…”

Metronidazole prevents reactivation of latentMycobacterium tuberculosisinfection in macaques

“…At necropsy, we obtained numerous samples from granulomas, lung lobes, thoracic lymph nodes, and extrapulmonary sites and used quantitative tools we developed and described in detail previously to score gross pathology, bacterial burden, and dissemination (19). These scoring systems distinguish clinically defined active, latent, and reactivated TB in macaques (19,21). The outbred nature of macaques introduces substantial variability among animals in terms of disease progression and response to therapies, just as in humans, which makes this a challenging but realistic model for testing therapeutics.…”

Global evidence directing regional preventive strategies in Southeast Asia for fighting TB/HIV

“…Lawn et al showed that the HIV-infected individuals with fewer peripheral CD4 + T cells are more prone to TB than HIV-infected individuals with relatively higher CD4 + T cells [10]. Furthermore, the study of Diedrich et al reported that the reactivation of latent M. tuberculosis in cynomolgus macaques infected with simian immunodeficiency virus (SIV) is associated with early peripheral T cell depletion even before the rise in SIV viral load [11].…”