Dynamics and consequences of IL-21 production in HIV-infected individuals: a longitudinal and cross-sectional study.
IL-21 is a relatively newly discovered immune-enhancing cytokine that plays an essential role in controlling chronic viral infections. It is produced mainly by CD4(+) T cells, which are also the main targets of HIV-1 and are often depleted in HIV-infected individuals. Therefore, we sought to determine the dynamics of IL-21 production and its potential consequences for the survival of CD4(+) T cells and frequencies of HIV-specific CTL. For this purpose, we conducted a series of cross-sectional and longitudinal studies on different groups of HIV-infected patients and show in this study that the cytokine production is compromised early in the course of the infection. The serum cytokine concentrations correlate with CD4(+) T cell counts in the infected persons. Among different groups of HIV-infected individuals, only elite controllers maintain normal production of the cytokine. Highly active antiretroviral therapy only partially restores the production of this cytokine. Interestingly, HIV infection of human CD4(+) T cells inhibits cytokine production by decreasing the expression of c-Maf in virus-infected cells, not in uninfected bystander cells. We also show that the frequencies of IL-21-producing HIV-specific, but not human CMV-specific, Ag-experienced CD4(+) T cells are decreased in HIV-infected viremic patients. Furthermore, we demonstrate in this study that recombinant human IL-21 prevents enhanced spontaneous ex vivo death of CD4(+) T cells from HIV-infected patients. Together, our results suggest that serum IL-21 concentrations may serve as a useful biomarker for monitoring HIV disease progression and the cytokine may be considered for immunotherapy in HIV-infected patients.
Iannello
Alexandre
A
Laboratory of Innate Immunity, Centre Hospitalier Universitaire Sainte-Justine Research Center, University of Montreal, Montreal, Canada.
Boulassel
Mohamed-Rachid
MR
Samarani
Suzanne
S
Debbeche
Olfa
O
Tremblay
Cécile
C
Toma
Emil
E
Routy
Jean-Pierre
JP
Ahmad
Ali
A
D048868:Adaptor Proteins, Signal Transducing; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers / Q000032:analysis*; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis; D003430:Cross-Sectional Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D008137:Longitudinal Studies; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D000098546:Interleukin-21
D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; C540426:CMIP protein, human; D002352:Carrier Proteins; D007378:Interleukins; D034741:RNA, Small Interfering; D000098546:Interleukin-21