Simian Immunodeficiency Virus-Induced Changes in T Cell Cytokine Responses in Cynomolgus Macaques with Latent Mycobacterium tuberculosis Infection Are Associated with Timing of Reactivation

Abstract

Understanding the early immunologic events accompanying reactivated tuberculosis (TB) in HIV-infected individuals may yield insight into causes of reactivation and improve treatment modalities. We used the cynomolgus macaque (Macaca fascicularis) model of HIV–Mycobacterium tuberculosis coinfection to investigate the dynamics of multifunctional T cell responses and granuloma T cell phenotypes in reactivated TB. CD4+ and CD8+ T cells expressing Th1 cytokines (IFN-γ, IL-2, TNF) and Th2 cytokines (IL-4 and IL-10) were followed from latent M. tuberculosis infection to reactivation after coinfection with a pathogenic SIV. Coinfected animals experienced increased Th1 cytokine responses to M. tuberculosis Ags above the latent-response baseline 3–5 wk post-SIV infection that corresponded with peak plasma viremia. Th2 cytokine expression was not Ag specific, but strong, transient IL-4 expression was noted 4–7 wk post-SIV infection. Animals reactivating <17 wk post-SIV infection had significantly more multifunctional CD4+ T cells 3–5 wk post-SIV infection and more Th2-polarized and fewer Th0-, Th1-polarized CD8+ T cells during weeks 1–10 post-SIV infection than animals reactivating >26 wk post-SIV infection. Granuloma T cells included Th0-, Th1-, and Th2-polarized phenotypes but were particularly rich in cytolytic (CD107+) T cells. When combined with the changes in peripheral blood T cells, these factors indicate that events during acute HIV infection are likely to include distortions in proinflammatory and anti-inflammatory T cell responses within the granuloma that have significant effects on reactivation of latent TB. Moreover, it appears that mycobacteria-specific multifunctional T cells are better correlates of Ag load (i.e., disease status) than of protection.

Modeling Tuberculosis in Nonhuman Primates

“…Although the Erdman strain of M. tuberculosis appears more virulent in NHPs because of its ability to cause progressive TB in both rhesus (Langermans et al 2001;Gormus et al 2004;Sharpe et al 2009Sharpe et al , 2010 and cynomolgus (Walsh et al 1996;Langermans et al 2001;Capuano et al 2003;Sharpe et al 2009;Lin et al , 2012b macaques, low doses (25 CFU) of Erdman in cynomolgus macaques lead to latent TB in half the monkeys (Lin et al 2009(Lin et al , 2012bDiedrich et al 2010;Mattila et al 2011). When larger inocula (250 -500 CFU) of the same Erdman strain were similarly delivered to cynomolgus macaques, all progressed to active TB (Lin et al 2012b;Chen et al 2013).…”

Monkey Models of Tuberculosis: Lessons Learned

“…A series of subsequent investigations were dedicated to macaque research to assess novel TB vaccines and drugs, as well as to gain an understanding of the pathogenesis of M. tuberculosis infection and reactivation. Figures 2 and 3 abridge the RM (13,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43) and CM (10,15,25,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59) models of experimental M. tuberculosis infection after the Golden Age, from 2001 to 2014.…”

HIV–TB coinfection impairs CD8+ T‐cell differentiation and function while dehydroepiandrosterone improves cytotoxic antitubercular immune responses

“…As the amount of DHEA in plasma and the intensity of the immune response to Mtb are determined by several factors (i.e. activation of hypothalamus-pituitary axis [14], TB burden [38], or HIV disease progression [25], among others), the association between DHEA plasma levels and Mtb-specific CD8 + T cells proportions in our cohort could be masked by these other factors.Contrary to our expectations, we detected a positive correlation between cortisol plasma levels and CD107a/b + CD8 + T cells in HIV-TB individuals (Fig. 4B).…”