Persistent alterations in T-cell repertoire, cytokine and chemokine receptor gene expression after 1 year of highly active antiretroviral therapy.
OBJECTIVE
To examine T-cell repertoire modifications, the evolution of T-helper (TH)1/TH2 cytokine imbalance and modifications in chemokine receptor expression when the viral load is decreased by 2-3 log10 copies/ml under highly active antiretroviral therapy (HAART).


METHODS
Sixteen patients previously treated with zidovudine and lamivudine, with CD4 cells below 300 x 10(6)/l and viraemia above 30000 copies/ml were treated by saquinavir and ritonavir together with both reverse transcriptase (RT) inhibitors (ANRS 069 trial). T-cell repertoire, chemokine receptor and lymphokine expression were studied from peripheral blood mononuclear cells sampled at weeks 0, 24 and 48.


METHODS
T-cell repertoire study was carried out using the Immunoscope method. Interleukin (IL)-12 receptor beta2, CC-chemokine receptor (CCR)-3, CXC-chemokine receptor-4 and CCR-5 expression in CD4+ cells was measured by kinetic quantitative PCR and IL-2, IL-4, IL-10, IL-13, interferon (IFN)-gamma were measured using a quantitative RT-PCR assay with homologous internal standards.


RESULTS
Repertoire alterations were more frequent in CD4- than in CD4+ cells and persisted despite undetectable viraemia. Increased CCR-3 expression and spontaneous IFN-gamma as well as mitogenic induced IL-13 were observed at baseline and decreased slightly under HAART.


CONCLUSIONS
The CD8+ cell repertoire alterations were profound, whereas the CD4+ cell alterations were moderate and both persisted unchanged under HAART. The TH1/TH2 imbalance was more related to TH2 over-expression than to TH1 deficiency and persisted for at least 1 year under HAART.
Martinon
F
F
ICGM-INSERM U445, Hôpital Cochin, Paris, France.
Michelet
C
C
Peguillet
I
I
Taoufik
Y
Y
Lefebvre
P
P
Goujard
C
C
Guillet
J G
JG
Delfraissy
J F
JF
Lantz
O
O
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D018793:Interleukin-13 / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D019259:Lamivudine / Q000627:therapeutic use; D008137:Longitudinal Studies; D008297:Male; D012333:RNA, Messenger; D054397:Receptors, CCR3; D019713:Receptors, CCR5 / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics*; D018123:Receptors, Interleukin / Q000235:genetics; D053707:Receptors, Interleukin-12; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D019438:Ritonavir / Q000627:therapeutic use; D019258:Saquinavir / Q000627:therapeutic use; D015215:Zidovudine / Q000627:therapeutic use
D019380:Anti-HIV Agents; C515350:CCR3 protein, human; D016207:Cytokines; D017320:HIV Protease Inhibitors; C508439:IL12RB2 protein, human; D018793:Interleukin-13; D007376:Interleukin-2; D012333:RNA, Messenger; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018894:Reverse Transcriptase Inhibitors; D016753:Interleukin-10; D015847:Interleukin-4; D019259:Lamivudine; D015215:Zidovudine; D007371:Interferon-gamma; D019258:Saquinavir; D019438:Ritonavir