Selective Impairments in Dendritic Cell-Associated Function Distinguish Hepatitis C Virus and HIV Infection

Abstract

Impaired APC functions may play important roles in chronicity of hepatitis C virus (HCV) and HIV infections. To investigate the separate and combined effects of HCV and HIV infection on immature dendritic cells (DCs), we evaluated myeloid-derived DC (MDC) and plasmacytoid-derived DC (PDC) frequencies and functions, measured by Toll-like receptor ligand-induced IFN-α and IL-12, in healthy controls and subjects with chronic HCV, HIV, and HCV-HIV infection. To evaluate the relation between innate and adaptive immunity, we measured HCV-specific IFN-γ-producing T cell frequency. MDC frequencies tended to be reduced in HIV infection (1.8-fold), while PDC frequencies were minimally reduced in HCV infection (1.4-fold). In contrast, a striking reduction in non-PDC-associated IFN-α production was observed in HIV-infected subjects (17-fold), while PDC-associated IFN-α production was markedly reduced in HCV-infected subjects (20-fold). Both non-PDC and PDC functions were impaired in HCV-HIV coinfection. MDC-associated IL-12 production was markedly reduced in both HCV and HIV-infected subjects (over 10-fold). Functional defects were attenuated with slowly progressive HIV infection. The proportion of subjects with HCV-specific T cell responses, and the number of Ags recognized were reduced in HCV-HIV subjects as compared with HCV singly infected subjects. A positive association was observed between MDC-associated IL-12 production and HCV-specific T cell frequency in HCV-infected subjects. These results indicate that immature DC function is dysregulated in HIV and HCV infections, but differentially, and that these defects are attenuated in slowly progressive HIV infection. These selectively different impairments may contribute to the reduced adaptive immune response to HCV in HCV-HIV coinfection.

Differential Restoration of Myeloid and Plasmacytoid Dendritic Cells in HIV-1-Infected Children after Treatment with Highly Active Antiretroviral Therapy

“…Freshly collected PBMC were stimulated with one of the following TLR ligands: TLR3L poly (I:C) or TLR9L CpG oligodeoxynucleotides (23,(32)(33)(34). Poly(I:C) stimulates mDCs to secrete IL-12 (23,33), whereas CpG stimulates pDCs to secrete IFN-␣ secretion (23,34).…”

“…Freshly prepared PBMC populations (2 ϫ 10 6 cells/0.5 ml/well) were stimulated in 24-well plates with medium alone, 50 g/ml poly(I:C) (Amersham), or 6 g/ml CpG 2216 (Sangon) for 24 h at 37°C in the presence of penicillin, streptomycin, L-glutamine, and 10% FCS (23). Cell-free supernatants were harvested and tested in duplicate for IFN-␣ or IL-12 by use of a commercial ELISA kit according to the manufacturer's instructions (BioSource International).…”

“…Freshly collected PBMC were stimulated with one of the following TLR ligands: TLR3L poly (I:C) or TLR9L CpG oligodeoxynucleotides (23,(32)(33)(34). Poly(I:C) stimulates mDCs to secrete IL-12 (23,33), whereas CpG stimulates pDCs to secrete IFN-␣ secretion (23,34). Our previous demonstrations that depletion of BDCA-1 ϩ cells (90% of mDC subset) and BDCA-4 ϩ cells (90% of pDC subset) from the total PBMC population markedly reduced poly(I:C)-induced IL-12 production and CpG-induced IFN-␣ production by almost 90%, respectively, indicates that we can use stimulated PBMC cytokine release as surrogate markers of mDC and pDC function.…”

Plasmacytoid dendritic cells in acute and chronic hepatitis C virus infection

“…12,14 In cHC, an impairment of monocyte-derived dendritic cells has been suggested in several studies [15][16][17][18] and could be due to direct infection of these cells by HCV. 19 Along these lines, infection of pDCs, 20 a reduced relative frequency of pDCs, and a reduced capacity to produce IFN-␣ have recently been shown in cHC [21][22][23] and during IFN-␣ treatment, 24 but their relevance-particularly during the acute phase of HCV infection, when the decision of viral clearance versus persistence is made-has not been studied.…”

Experimental models to study the immunobiology of hepatitis C virus

“…Similarly, while some studies suggested that the functionality of DCs was impaired during chronic infection, e.g. mDCs being poor activators of CD4 + T cells (AuffermannGretzinger et al, 2001;Bain et al, 2001;Dolganiuc et al, 2008;Kanto et al, 1999) and pDCs producing less IFN-a (Anthony et al, 2004;Yonkers et al, 2007), other studies reported that mDCs and pDCs from chronically infected patients remained functional (Decalf et al, 2007;Lai et al, 2007;Longman et al, 2004). It is interesting to note that, however, several groups have reported that the frequency of circulating mDCs and pDCs during chronic HCV infection is reduced, probably due to an intrahepatic enrichment (Dolganiuc et al, 2006;Lai et al, 2007;Mengshol et al, 2009;Nattermann et al, 2006;Wertheimer et al, 2004).…”