Impaired IFN-gamma-secreting capacity in mycobacterial antigen-specific CD4 T cells during chronic HIV-1 infection despite long-term HAART.
OBJECTIVE
To determine whether long-term HAART in chronic HIV-1 infection restores fully functional Mycobacterium tuberculosis (MTB)-specific CD4 T-cell responses.


METHODS
A cross-sectional study of HIV-1-seropositive subjects on continuous HAART for over one year with CD4 cell counts greater than 300 cells/microl and undetectable viraemia, antiretroviral-naive individuals with primary HIV-1 infection (PHI), and healthy bacillus Calmette-Guérin-vaccinated low-risk controls.


METHODS
Purified protein derivative (PPD)-specific cytokine-secreting CD4 T cells were quantified ex vivo by enzyme-linked immunospot assay and intracellular cytokine staining. Lymphoproliferation was detected by [3H]-thymidine incorporation.


RESULTS
PPD-specific IFN-gamma-secreting CD4 T cells were markedly reduced in chronic HAART-treated HIV-1-positive and PHI subjects compared with healthy controls [medians 30, 155 and 582 spot-forming cells/million peripheral blood mononuclear cells (PBMC), respectively, P < 0.0001 and P < 0.002], but the frequency of these cells was, nonetheless, significantly greater in viraemic PHI subjects than in aviraemic chronic HIV-1-positive subjects (P < 0.01). In the latter, low frequencies of PPD-specific IL-2 and IL-4-secreting CD4 T cells were also observed. However, lymphoproliferation was evident after the in-vitro stimulation of PBMC with PPD, indicating that MTB-specific T cells were present. The defect in IFN-gamma secretion could be overcome by culture with IL-12.


CONCLUSIONS
Despite an improvement in CD4 T-cell counts after HAART, MTB-specific CD4 T cells from chronically infected patients have impaired IFN-gamma-secreting capacity. The early initiation of HAART might preserve functional CD4 T-cell responses to MTB, and warrants evaluation in populations with a high risk of dual infection.
MRC Human Immunology Unit, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford OX3 7LJ, UK.
Rebecca
R
Sutherland
Hongbing
H
Yang
Thomas J
TJ
Scriba
Beatrice
B
Ondondo
Nicola
N
Robinson
Christopher
C
Conlon
Annie
A
Suttill
Helen
H
McShane
Sarah
S
Fidler
Andrew
A
McMichael
Lucy
L
Dorrell
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002908:Chronic Disease; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology; D014373:Tuberculin / Q000276:immunology
D019380:Anti-HIV Agents; D007376:Interleukin-2; D014373:Tuberculin; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma