Dendritic cell function during chronic hepatitis C virus and human immunodeficiency virus type 1 infection.
Hepatitis C virus (HCV) infection can persist despite HCV-specific T-cell immunity and can have a more aggressive course in persons coinfected with human immunodeficiency virus type 1 (HIV-1). Defects in antigen-presenting, myeloid dendritic cells (DCs) could underlie this T-cell dysfunction. Here we show that monocyte-derived DCs from persons with chronic HCV infection, with or without HIV-1 coinfection, being treated with combination antiretroviral therapy produced lower levels of interleukin 12 (IL-12) p70 in response to CD40 ligand (CD40L), whereas the expression of DC surface activation and costimulatory molecules was unimpaired. The deficiency in IL-12 production could be overcome by addition of gamma interferon (IFN-gamma) with CD40L, resulting in very high, comparable levels of IL-12 production by DCs from HCV- and HIV-1-infected subjects. Smaller amounts of IL-12 p70 were produced by DCs treated with the immune modulators tumor necrosis factor alpha and IL-1beta, with or without IFN-gamma, and the amounts did not differ among the uninfected and infected subjects. Blocking of IL-10 with an anti-IL-10 monoclonal antibody in the CD40L-stimulated DC cultures from HCV-infected persons increased the level of IL-12 p70 production. The ability of DCs from HCV-infected persons to stimulate allogeneic CD4+ T cells or induce IL-2, IL-5, or IL-10 in a mixed lymphocyte reaction was not impaired. Thus, myeloid DCs derived from persons with chronic HCV infection or with both HCV and HIV-1 infections have defects in IL-12 p70 production related to IL-10 activity that can be overcome by treatment of the DCs with CD40L and IFN-gamma. DCs from these infected subjects have a normal capacity to stimulate CD4+ T cells. The functional effectiveness of DCs derived from HCV-infected individuals provides a rationale for the DC-based immunotherapy of chronic HCV infection.
Fan
Zheng
Z
Graduate School of Public Health and School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Huang
Xiao-Li
XL
Kalinski
Pawel
P
Young
Stephen
S
Rinaldo
Charles R
CR
D023201:CD40 Ligand / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D015658:HIV Infections / Q000150:complications* / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000276:immunology* / Q000821:virology; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D018664:Interleukin-12 / Q000276:immunology; D053583:Interleukin-1beta / Q000494:pharmacology; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D053583:Interleukin-1beta; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma