Defective dendritic cell function in HIV-infected patients receiving effective highly active antiretroviral therapy: neutralization of IL-10 production and depletion of CD4+CD25+ T cells restore high levels of HIV-specific CD4+ T cell responses induced by dendritic cells generated in the presence of IFN-alpha.
We previously demonstrated that GM-CSF/IFN-alpha combination allowed the differentiation of monocytes from HIV-infected patients into dendritic cells (DCs) exhibiting high CD8(+) T cell stimulating abilities. The present study was aimed at characterizing the ability of DCs generated in the presence of GM-CSF and IFN-alpha to induce CD4 T cell responses. DCs were generated from monocytes of HIV-infected patients in the presence of GM-CSF with either IFN-alpha (IFN-DCs) or IL-4 (IL-4-DCs) for 7 days. Eleven patients receiving highly active antiretroviral therapy and exhibiting CD4 cell counts above 400/mm(3) and plasma HIV-RNA <50 copies/ml for at least 1 year were included in the study. Both DC populations were found to be defective in inducing autologous (in response to tuberculin or HIV-p24) or allogeneic CD4 T cell proliferation. Neutralization of IL-10 during the differentiation of IFN-DCs, but not during the DC-T cell coculture, significantly increased their ability to stimulate autologous CD4 T cell proliferation in response to tuberculin and allogeneic CD4 T cell proliferation (4.1-fold and 3.0-fold increases, respectively, at the DC to T cell ratio of 1:10). Moreover, IL-10 neutralization and CD4(+)CD25(+) T cell depletion synergistically act to dramatically increase HIV-p24-specific CD4 T cell responses induced by IFN-DCs (31.7-fold increase) but not responses induced by IL-4-DCs. Taken together, our results indicate that IFN-DCs are more efficient than IL-4-DCs to stimulate CD4(+) T cell proliferation, further supporting their use for immune-based therapy in HIV infection.
Carbonneil
Cédric
C
Institut National de la Santé et de la Recherche Médicale Unité 430, Institut des Cordeliers, Paris, France.
Donkova-Petrini
Vladimira
V
Aouba
Albertine
A
Weiss
Laurence
L
D017951:Antigen Presentation; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation; D002469:Cell Separation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016655:HIV Core Protein p24 / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D009000:Monocytes / Q000473:pathology; D015375:Receptors, Interleukin-2 / Q000032:analysis
D016655:HIV Core Protein p24; D016898:Interferon-alpha; D015375:Receptors, Interleukin-2; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma