Dissection of regenerating T-Cell responses against tuberculosis in HIV-infected adults sensitized by Mycobacterium tuberculosis.
BACKGROUND
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.


OBJECTIVE
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.


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-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).


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.
Wilkinson
Katalin A
KA
Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Room S3.13, Wernher & Beit Building South, Observatory 7925, Republic of South Africa. katalin.wilkinson@uct.ac.za
Seldon
Ronnett
R
Meintjes
Graeme
G
Rangaka
Molebogeng X
MX
Hanekom
Willem A
WA
Maartens
Gary
G
Wilkinson
Robert J
RJ
D000328:Adult; D000480:Alkynes; D000704:Analysis of Variance; D019380:Anti-HIV Agents / Q000627:therapeutic use; D044966:Anti-Retroviral Agents / Q000097:blood / Q000627:therapeutic use*; D048588:Benzoxazines / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count / Q000379:methods; D003521:Cyclopropanes; D016207:Cytokines / Q000187:drug effects; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007114:Immunization; D019259:Lamivudine / Q000627:therapeutic use; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D019829:Nevirapine / Q000627:therapeutic use; D018119:Stavudine / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014376:Tuberculosis / Q000097:blood / Q000276:immunology* / Q000517:prevention & control*
D000480:Alkynes; D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D016207:Cytokines; D019259:Lamivudine; D019829:Nevirapine; D018119:Stavudine; C098320:efavirenz