Dissection of Regenerating T-Cell Responses against Tuberculosis in HIV-infected Adults Sensitized by Mycobacterium tuberculosis

Abstract

Combination antiretroviral treatment (cART) reduces the risk of tuberculosis in HIV-infected people. Therefore a novel approach to gain insight into protection against tuberculosis is to analyze the T cells that expand in people sensitized by Mycobacterium tuberculosis (MTB) during cART. To longitudinally analyze CD4 T-cell subsets during the first year of cART, from the time of starting cART (Day 0), in 19 HIV-infected, MTB-sensitized adults. Peripheral blood mononuclear cells were obtained on Day 0, Weeks 2, 4, 12, 24, 36, and 48 of cART and were stimulated with purified protein derivative (PPD) followed by flow cytometry to analyze surface markers and intracellular cytokines. CD4(+) T cells significantly increased during follow-up and the viral load fell to undetectable levels in each patient, indicating successful immune restoration. Central memory CD27(+)CD45RA(-) and CD27(+)CCR5(-) CD4(+) cells expanded by 12 weeks (P < 0.02) followed by naive CD27(+)CD45RA(+) cells at 36 weeks (P = 0.02). Terminally differentiated effector CD4(+)CD27(-)CCR7(-) cells decreased by 12 weeks (P = 0.02), paralleled by a proportional decline of PPD-specific CD4(+)IFN-gamma(+) cells (P = 0.02). However, the absolute numbers of PPD-specific IFN-gamma-producing cells, determined by enzyme-linked immunospot assay, increased (P = 0.02). Rapid effector responses are often measured when evaluating immunity. We show that although cART is associated with an absolute increase in effector function, the proportional response decreased and the strongest correlate of increased cART-mediated immunity in this study was the central memory response.