Publications (5)40.03 Total impact
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Article: IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B.
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ABSTRACT: HBV is a noncytopathic hepadnavirus and major human pathogen that causes immune-mediated acute and chronic hepatitis. The immune response to HBV antigens is age dependent: viral clearance occurs in most adults, while neonates and children usually develop chronic infection and liver disease. Here, we characterize an animal model for HBV infection that recapitulates the key differences in viral clearance between early life and adulthood and find that IL-21 may be part of an effective primary hepatic immune response to HBV. In our model, adult mice showed higher HBV-dependent IL-21 production in liver, compared with that of young mice. Conversely, absence of the IL-21 receptor in adult mice resulted in antigen persistence akin to that of young mice. In humans, levels of IL-21 transcripts were greatly increased in blood samples from acutely infected adults who clear the virus. These observations suggest a different model for the dichotomous, age dependent outcome of HBV infection in humans, in which decreased IL-21 production in younger patients may hinder generation of crucial CD8+ T and B cell responses. These findings carry implications for therapeutic augmentation of immune responses to HBV and potentially other persistent liver viruses.The Journal of clinical investigation 02/2011; 121(3):1154-62. · 15.39 Impact Factor -
Article: A case-control study of factors associated with resolution of hepatitis C viremia in former blood donors (CME).
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ABSTRACT: Nucleic acid testing (NAT) is performed on blood collected in the United States allowing for the classification of hepatitis C virus (HCV) antibody-positive donors into resolved and chronic hepatitis C infections. We report a case-control study of factors associated with HCV resolution. Blood donors with resolved (HCV antibody positive, RNA negative defined as "cases") or chronic (HCV antibody positive, RNA positive defined as "controls") based on their index donation HCV test results were enrolled. Participants completed a risk factor, symptoms, and treatment questionnaire followed by HCV antibody, HCV RNA, and liver biochemical testing. We enrolled 100 cases and 202 controls. In a multivariate logistic regression model, significant independent effects for spontaneous viral clearance were observed for African American (inverse; odds ratio [OR], 0.11; 95% confidence interval [CI], 0.01-0.87), autologous blood donation (OR, 4.70; 95% CI, 2.02-10.94), alcohol intake (OR, 2.39; 95% CI, 1.13-5.03), and transfusion before May 1990 (inverse; OR, 0.36; 95% CI, 0.14-0.91). Cases admitting injection drug use had shorter time since first injection than did controls. Forty-nine index RNA positive controls received antiviral therapy and 25 (51%) were RNA negative at enrollment; surprisingly several RNA-negative cases received liver biopsies and/or antiviral treatment. We document the role donor screening plays in the identification, subsequent medical evaluation, and treatment among individuals who presumably did not know that they were at risk for HCV infection. Additionally, we confirmed race/ethnicity as a determinant of clearance and suggest infectious dose and route of infection may play a role in clearance.Transfusion 03/2010; 50(7):1513-23. · 3.22 Impact Factor -
Article: Acute hepatitis C virus infection in young adult injection drug users: a prospective study of incident infection, resolution, and reinfection.
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ABSTRACT: Hepatitis C virus (HCV) infection, clearance, and reinfection are best studied in injection drug users (IDUs), who have the highest incidence of HCV and are likely to represent most infections. A prospective cohort of HCV-negative young IDUs was followed up from January 2000 to September 2007, to identify acute and incident HCV and prospectively study infection outcomes. Among 1,191 young IDUs screened, 731 (61.4%) were HCV negative, and 520 (71.1%) of the 731 were enrolled into follow-up. Cumulative HCV incidence was 26.7/100 person-years of observation (95% confidence interval [CI], 21.5-31.6). Of 135 acute/incident HCV infections, 95 (70.4%) were followed; 20 (21.1%) of the 95 infections cleared. Women had a significantly higher incidence of viral clearance than did men (age-adjusted hazard ratio, 2.91 [95% CI, 1.68-5.03]) and also showed a faster rate of early HCV viremia decline (P < .01). The estimated reinfection rate was 24.6/100 person-years of observation (95% CI, 11.7-51.6). Among 7 individuals, multiple episodes of HCV reinfection and reclearance were observed. In this large sample of young IDUs, females show demonstrative differences in their rates of viral clearance and kinetics of early viral decline. Recurring reinfection and reclearance suggest possible protection against persistent infection. These results should inform HCV clinical care and vaccine development.The Journal of Infectious Diseases 10/2009; 200(8):1216-26. · 6.41 Impact Factor -
Article: High levels of subgenomic HCV plasma RNA in immunosilent infections.
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ABSTRACT: A genetic analysis of hepatitis C virus (HCV) in rare blood donors who remained HCV seronegative despite long-term high-level viremia revealed the chronic presence of HCV genomes with large in frame deletions in their structural genes. Full-length HCV genomes were only detected as minority variants. In one immunodeficiency virus (HIV) co-infected donor the truncated HCV genome transiently decreased in frequency concomitant with delayed seroconversion and re-emerged following partial seroreversion. The long-term production of heavily truncated HCV genomes in vivo suggests that these viruses retained the necessary elements for RNA replication while the deleted structural functions necessary for their spread in vivo was provided in trans by wild-type helper virus in co-infected cells. The absence of immunological pressure and a high viral load may therefore promote the emergence of truncated HCV subgenomic replicons in vivo.Virology 10/2007; 365(2):446-56. · 3.35 Impact Factor -
Article: Interferon alfa regulated gene expression in patients initiating interferon treatment for chronic hepatitis C.
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ABSTRACT: Interferon alfa (IFN-alpha) is an approved therapeutic agent for chronic hepatitis C. To directly characterize the effects of IFN-alpha in humans, we used microarrays to profile gene expression in peripheral blood mononuclear cells (PBMCs) from hepatitis C patients treated with IFN-alpha. Seven patients were studied using two strategies: (1) in vivo: PBMCs were collected immediately before the first dose of IFN-alpha, and 3 and 6 hours after the dose; (2) ex vivo: PBMCs that were collected before the first IFN-alpha dose were incubated with IFN-alpha for 3 and 6 hours. The microarray datasets were analyzed with significance analysis of microarrays (SAM) to identify genes regulated by IFN-alpha. We identified 516 named genes up-regulated at least 2-fold, at a false discovery rate (FDR) of less than 1%. In vivo and ex vivo studies generated similar results. No genes were identified as regulated differently between these 2 experimental conditions. The up-regulated genes belonged to a broad range of functional pathways and included multiple genes thought to be involved in the direct antiviral effect of IFN-alpha. Of particular interest, 88 genes directly relating to functions of immune cells were up-regulated, including genes involved in antigen processing and presentation, T-cell activation, lymphocyte trafficking, and effector functions, suggesting that IFN-alpha up-regulates multiple genes involving different aspects of immune responses to enhance immunity against hepatitis C virus. In conclusion, IFN-alpha-inducible genes can be identified in human PBMCs in vivo as well as ex vivo. Signature changes associated with different treatment outcomes may be found among these genes.Hepatology 04/2003; 37(3):610-21. · 11.66 Impact Factor
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2003
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University of California, San Francisco
- Division of Hospital Medicine
San Francisco, CA, USA
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