Human Immunodeficiency Virus Infection Impairs Th1 and Th17 Mycobacterium tuberculosis-Specific T-Cell Responses

Background. Human immunodeficiency virus (HIV)-infected individuals have a higher risk of developing active tuberculosis (TB) than HIV-uninfected individuals, but the mechanisms underpinning this are unclear. We hypothesized that depletion of specific components of Mycobacterium tuberculosis (Mtb)-specific CD4(+) and CD8(+) T-cell responses contributed to this increased risk. Methods. Mtb-specific T-cell responses in 147 HIV-infected and 44 HIV-uninfected control subjects in a TB-endemic setting in Bloemfontein, South Africa, were evaluated. Using a whole-blood flow cytometry assay, we measured expression of interferon gamma, tumor necrosis factor alpha, interleukin 2, and interleukin 17 in CD4(+) and CD8(+) T cells in response to Mtb antigens (PPD, ESAT-6/CFP-10 [EC], and DosR regulon-encoded a-crystallin [Rv2031c]). Results. Fewer HIV-infected individuals had detectable CD4(+) and CD8(+) T-cell responses to PPD and Rv2031c than HIV-uninfected subjects. Mtb-specific T cells showed distinct patterns of cytokine expression comprising both Th1 (CD4 and CD8) and Th17 (CD4) cytokines, the latter at highest frequency for Rv2031c. Th17 antigen-specific responses to all antigens tested were specifically impaired in HIV-infected individuals. Conclusions. HIV-associated impairment of CD4(+) and CD8(+) Mtb-specific T-cell responses is antigen specific, particularly impacting responses to PPD and Rv2031c. Preferential depletion of Th17 cytokine-expressing CD4(+) T cells suggests this T-cell subset may be key to TB susceptibility in HIV-infected individuals.