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Sustained hyperresponsiveness of dendritic cells is associated with spontaneous resolution of acute hepatitis C.

ABSTRACT: Some studies have reported that dendritic cells (DCs) may be dysfunctional in a subset of patients with chronic hepatitis C virus (HCV) infection. However, the function of DCs during acute HCV infection and their role in determining infectious outcome remain elusive. Here, we examined the phenotype and function of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) during acute HCV infection. Three groups of injection drug users (IDUs) at high risk of HCV infection were studied: an uninfected group, a group with acute HCV infection with spontaneous resolution, and a group with acute infection with chronic evolution. We examined the frequency, maturation status, and cytokine production capacity of DCs in response to the Toll-like receptor 4 (TLR4) and TLR7/8 ligands lipopolysaccharide (LPS) and single-stranded RNA (ssRNA), respectively. Several observations could distinguish HCV-negative IDUs and acute HCV resolvers from patients with acute infection with chronic evolution. First, we observed a decrease in the frequency of mature CD86(+), programmed death-1 receptor ligand-positive (PDL1(+)), and PDL2(+) pDCs. This phenotype was associated with the increased sensitivity of pDCs from resolvers and HCV-negative IDUs versus the group with acute infection with chronic evolution to ssRNA stimulation in vitro. Second, LPS-stimulated mDCs from resolvers and HCV-negative IDUs produced higher levels of cytokines than mDCs from the group with acute infection with chronic evolution. Third, mDCs from all patients with acute HCV infection, irrespective of their outcomes, produced higher levels of cytokines during the early acute phase in response to ssRNA than mDCs from healthy controls. However, this hyperresponsiveness was sustained only in spontaneous resolvers. Altogether, our results suggest that the immature pDC phenotype and sustained pDC and mDC hyperresponsiveness are associated with spontaneous resolution of acute HCV infection.

SUBMITTER: Pelletier S

PROVIDER: S-EPMC3676083 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Sustained hyperresponsiveness of dendritic cells is associated with spontaneous resolution of acute hepatitis C.

Pelletier Sandy S Bédard Nathalie N Said Elias E Ancuta Petronela P Bruneau Julie J Shoukry Naglaa H NH

Journal of virology 20130410 12

Some studies have reported that dendritic cells (DCs) may be dysfunctional in a subset of patients with chronic hepatitis C virus (HCV) infection. However, the function of DCs during acute HCV infection and their role in determining infectious outcome remain elusive. Here, we examined the phenotype and function of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) during acute HCV infection. Three groups of injection drug users (IDUs) at high risk of HCV infection were studied: an uninfected group, ...[more]

PMID: 23576504

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Project description:Hepatitis C virus (HCV) frequently causes chronic hepatitis, while spontaneous recovery from infection is infrequent. Persistence of HCV after self-limited (spontaneous) resolution of hepatitis C was rarely investigated. The current study aimed to assess incidence and robustness of HCV persistence after self-resolved hepatitis C in individuals with normal liver enzymes and undetectable virus by conventional tests. Applying high sensitivity HCV RNA detection approaches, we analyzed plasma and peripheral blood mononuclear cells (PBMC) from individuals with previous hepatitis C infection. Parallel plasma and PBMC from 24 such non-viraemic individuals followed for 0.3-14.4 (mean 6.4) years were examined. Additional samples from 9 of them were obtained 4.5-7.2 (mean 5.9) years later. RNA was extracted from 250 ?l plasma and, if HCV negative, from ~5 ml after ultracentrifugation, and from ex vivo stimulated PBMC. PBMC with evidence of HCV replication from 4 individuals were treated with HCV protease inhibitor, telaprevir. HCV RNA was detected in 14/24 (58.3%) plasma and 11/23 (47.8%) PBMC obtained during the first collection. HCV RNA replicative strand was evident in 7/11 (63.6%) PBMC. Overall, 17/24 (70.8%) individuals carried HCV RNA at mean follow-up of 5.9 years. Samples collected 4.5-7.2 years later revealed HCV in 4/9 (44.4%) plasma and 5/9 (55.5%) PBMC, while 4 (80%) of these 5 PBMC demonstrated virus replicative strand. Overall, 6/9 (66.7%) individuals remained viraemic for up to 20.7 (mean 12.7) years. Telaprevir entirely eliminated HCV replication in the PBMC examined. In conclusion, our results indicate that HCV can persist long after spontaneous resolution of hepatitis C at levels undetectable by current testing. An apparently effective host immune response curtailing hepatitis appears insufficient to completely eliminate the virus. The long-term morbidity of asymptomatic HCV carriage should be examined even in individuals who achieve undetectable HCV by standard testing and their need for treatment should be assessed.

Project description:Viral and/or host factors that are directly responsible for the acute versus chronic outcome of hepatitis B virus (HBV) infection have not been identified yet. Information on immune response during the early stages of HBV infection in humans is mainly derived from blood samples of patients with acute hepatitis B (AHB), which are usually obtained after the onset of clinical symptoms. Features of intrahepatic immune response in these patients are less studied due to the difficulty of obtaining multiple liver biopsies. Woodchuck hepatitis virus (WHV) infection in woodchucks is a model for HBV infection in humans. In the present study, five adult woodchucks were experimentally infected with WHV and then followed for 18 weeks. Blood and liver tissues were frequently collected for assaying markers of WHV replication and innate and adaptive immune responses. Liver tissues were further analyzed for pathological changes and stained for important immune cell subsets and cytokines. The increase and subsequent decline of viral replication markers in serum and liver, the elicitation of antibodies against viral proteins, and the induction of virus-specific T-cell responses indicated eventual resolution of acute WHV infection in all animals. Intrahepatic innate immune makers stayed unchanged immediately after the infection, but increased markedly during resolution, as determined by changes in transcript levels. The presence of interferon-gamma and expression of natural killer (NK) cell markers suggested that a non-cytolytic response mechanism is involved in the initial viral control in liver. This was followed by the expression of T-cell markers and cytolytic effector molecules, indicating the induction of a cytolytic response mechanism. Parallel increases in regulatory T-cell markers suggested that this cell subset participates in the overall immune cell infiltration in liver and/or has a role in regulating AHB induced by the cytolytic response mechanism. Since the transcript levels of immune cell markers in blood, when detectable, were lower than in liver, and the kinetics, except for NK-cells and interferon-gamma, did not correlate well with their intrahepatic expression, this further indicated enrichment of immune cells within liver. Conclusion: The coordinated interplay of innate and adaptive immunity mediates viral clearance in the woodchuck animal model of HBV infection. The initial presence of NK-cell associated interferon-gamma response points to an important role of this cytokine in HBV resolution.

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Sustained hyperresponsiveness of dendritic cells is associated with spontaneous resolution of acute hepatitis C.

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Sustained hyperresponsiveness of dendritic cells is associated with spontaneous resolution of acute hepatitis C.

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