HIV infection functionally impairs Mycobacterium tuberculosis-specific CD4 and CD8 T-cell responses

Human immunodeficiency virus (HIV) infection is the major risk factor predisposing for; Mycobacterium tuberculosis; progression from latent tuberculosis infection (LTBI) to tuberculosis disease (TB). Since long-term-treated aviremic HIV-infected individuals remained at higher risk of developing TB than HIV-uninfected individuals, we hypothesized that progression from LTBI to pulmonary TB (PTB) might be due not only to CD4 T-cell depletion but also to; M. tuberculosis; -specific CD4 T-cell functional impairment. To test this hypothesis,; M. tuberculosis; -specific T-cell frequencies and cytokine profiles were investigated in untreated Tanzanian individuals suffering from LTBI (; n; = 20) or PTB (; n; = 67) and compared to those of untreated; M. tuberculosis; /HIV-coinfected individuals suffering from LTBI (; n; = 15) or PTB (; n; = 10). We showed that HIV infection significantly reduced the proportion of Th2 (interleukin 4 [IL-4]/IL-5/IL-13) producing; M. tuberculosis; -specific CD4 T cells and IL-2-producing; M. tuberculosis; -specific CD4 and CD8 T cells in individuals with LTBI or PTB (; P < ; 0.05). Interestingly, the loss of IL-2 production was associated with a significant increase of PD-1 expression on; M. tuberculosis; -specific CD4 and CD8 T cells (; P < ; 0.05), while the loss of Th2 cytokine production was associated with a significant reduction of Gata-3 expression in memory CD4 T cells (; P < ; 0.05). Finally, we showed that the serum levels of IL-1α, IL-6, C-reactive protein (CRP), IL-23, and IP-10 were significantly reduced in; M. tuberculosis; /HIV-coinfected individuals with PTB compared to those in HIV-negative individuals with PTB (; P < ; 0.05), suggesting that HIV infection significantly suppresses; M. tuberculosis; -induced systemic proinflammatory cytokine responses. Taken together, this study suggests that in addition to depleting; M. tuberculosis; -specific CD4 T cells, HIV infection significantly impairs functionally favorable; M. tuberculosis; -specific CD4 T-cell responses in Tanzanian individuals with LTBI or PTB.; IMPORTANCE; Mycobacterium tuberculosis; and human immunodeficiency virus (HIV) infections are coendemic in several regions of the world, and; M. tuberculosis; /HIV-coinfected individuals are more susceptible to progression to tuberculosis disease. We therefore hypothesized that HIV infection would potentially impair; M. tuberculosis; -specific protective immunity in individuals suffering from latent tuberculosis infection (LTBI) or active pulmonary tuberculosis (PTB). In this study, we demonstrated that; M. tuberculosis; /HIV-coinfected individuals have fewer circulating; M. tuberculosis; -specific CD4 T cells and that those that remained were functionally impaired in both LTBI and PTB settings. In addition, we showed that HIV infection significantly interferes with; M. tuberculosis; -induced systemic proinflammatory cytokine/chemokine responses. Taken together, these data suggest that HIV infection impairs functionally favorable; M. tuberculosis; -specific immunity.