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

¹ Institute of Infectious Diseases and Molecular Medicine, ³ Department of Medicine, and ⁵ School of Child and Adolescent Health, University of Cape Town, South Africa; ² National Institute for Medical Research, Mill Hill, London, United Kingdom; ⁴ Infectious Diseases Unit, GF Jooste Hospital, Cape Town, South Africa; and ⁶ Division of Medicine, Imperial College London, United Kingdom

Correspondence and requests for reprints should be addressed to Katalin A. Wilkinson, Ph.D., Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Room S3.13, Wernher & Beit Building South, Observatory 7925, Republic of South Africa. E-mail: katalin.wilkinson{at}uct.ac.za

Rationale: 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.

Objectives: 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.

Methods: 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.

Measurements and Main Results: 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-⁺ cells (P = 0.02). However, the absolute numbers of PPD-specific IFN-–producing cells, determined by enzyme-linked immunospot assay, increased (P = 0.02).

Conclusions: 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.

Key Words: bacterial infections • RNA viruses • drug therapy

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Antiretroviral treatment reduces the risk of tuberculosis (TB) in HIV-infected subjects, but mechanisms of protective cellular immunity to TB remain ill understood. Longitudinal analysis of immunocompromised HIV-infected subjects who undergo immune-reconstituting antiretroviral therapy represents a novel approach to understanding protective mechanisms in human TB. What This Study Adds to the Field We show that in the context of overall improved TB antigen-specific T-cell responses it is the central memory rather than effector memory response that best correlates with decreased susceptibility. This has important implications for TB vaccine design and efficacy.