HIV Infection Functionally Impairs Mycobacterium tuberculosis- specific CD4 and CD8 T-cell responses.

HIV infection is the major risk factor predisposing for Mycobacterium tuberculosis ( Mtb ) 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 as compared to HIV-uninfected individuals, we hypothesized that progression from LTBI to pulmonary TB (PTB) might not only be due to CD4 T-cell depletion but also to Mtb -specific CD4 T-cell functional impairment. To test this hypothesis, Mtb -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 Mtb /HIV co-infected individuals suffering from LTBI (n=15) or PTB (n=10). We showed that HIV infection significantly reduced the proportion of Th2 (IL-4/IL-5/IL-13) producing Mtb -specific CD4 T cells and IL-2 producing Mtb -specific CD4 and CD8 T cells in both 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 Mtb -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, CRP, IL-23 and IP-10 were significantly reduced in Mtb /HIV co-infected individuals with PTB as compared to HIV negative individuals with PTB ( P <0.05), suggesting that HIV infection significantly suppresses Mtb -induced systemic pro-inflammatory cytokine responses. Taken together, this study suggests that in addition to deplete Mtb -specific CD4 T cells, HIV infection significantly impairs functionally favorable Mtb -specific CD4 T-cell responses in Tanzanian individuals with LTBI or PTB. IMPORTANCE Mycobacterium tuberculosis ( Mtb ) and Human Immunodeficiency Virus (HIV) infections are co-endemic in several regions of the world and Mtb /HIV co-infected individuals are more susceptible to progress to tuberculosis disease. We therefore hypothesized that HIV infection would potentially impair Mtb -specific protective immunity in individuals suffering from latent tuberculosis infection (LTBI) or active pulmonary tuberculosis (PTB). In this study, we demonstrated that Mtb /HIV co-infected individuals have less circulating Mtb -specific CD4 T cells and those that remained were functionally impaired in both LTBI and PTB settings. In addition, we showed that HIV infection significantly interferes with Mtb -induced systemic pro-inflammatory cytokine/chemokine responses. Taken together, these data suggest that HIV infection impairs functionally favorable Mtb -specific immunity.