HIV Infection Functionally Impairs Mycobacterium tuberculosis-Specific CD4 and CD8 T-Cell Responses

Abstract

Human immunodeficiency virus (HIV) infection is the major risk factor predisposing for <i>Mycobacterium tuberculosis</i> 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 <i>M. tuberculosis</i>-specific CD4 T-cell functional impairment. To test this hypothesis, <i>M. tuberculosis</i>-specific T-cell frequencies and cytokine profiles were investigated in untreated Tanzanian individuals suffering from LTBI (<i>n</i> = 20) or PTB (<i>n</i> = 67) and compared to those of untreated <i>M. tuberculosis</i>/HIV-coinfected individuals suffering from LTBI (<i>n</i> = 15) or PTB (<i>n</i> = 10). We showed that HIV infection significantly reduced the proportion of Th2 (interleukin 4 [IL-4]/IL-5/IL-13) producing <i>M. tuberculosis</i>-specific CD4 T cells and IL-2-producing <i>M. tuberculosis</i>-specific CD4 and CD8 T cells in individuals with LTBI or PTB (<i>P < </i>0.05). Interestingly, the loss of IL-2 production was associated with a significant increase of PD-1 expression on <i>M. tuberculosis</i>-specific CD4 and CD8 T cells (<i>P < </i>0.05), while the loss of Th2 cytokine production was associated with a significant reduction of Gata-3 expression in memory CD4 T cells (<i>P < </i>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 <i>M. tuberculosis</i>/HIV-coinfected individuals with PTB compared to those in HIV-negative individuals with PTB (<i>P < </i>0.05), suggesting that HIV infection significantly suppresses <i>M. tuberculosis</i>-induced systemic proinflammatory cytokine responses. Taken together, this study suggests that in addition to depleting <i>M. tuberculosis</i>-specific CD4 T cells, HIV infection significantly impairs functionally favorable <i>M. tuberculosis</i>-specific CD4 T-cell responses in Tanzanian individuals with LTBI or PTB.<b>IMPORTANCE</b><i>Mycobacterium tuberculosis</i> and human immunodeficiency virus (HIV) infections are coendemic in several regions of the world, and <i>M. tuberculosis</i>/HIV-coinfected individuals are more susceptible to progression to tuberculosis disease. We therefore hypothesized that HIV infection would potentially impair <i>M. tuberculosis</i>-specific protective immunity in individuals suffering from latent tuberculosis infection (LTBI) or active pulmonary tuberculosis (PTB). In this study, we demonstrated that <i>M. tuberculosis</i>/HIV-coinfected individuals have fewer circulating <i>M. tuberculosis</i>-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 <i>M. tuberculosis</i>-induced systemic proinflammatory cytokine/chemokine responses. Taken together, these data suggest that HIV infection impairs functionally favorable <i>M. tuberculosis</i>-specific immunity.