During hepatitis C virus (HCV) infection, broadly neutralizing antibody (bNAb) responses targeting E1E2 envelope glycopro-teins are generated in many individuals. It is unclear if these antibodies play a protective or a pathogenic role during chronic infection. In this study, we investigated whether bNAb responses in individuals with chronic infection were associated with differences in clinical presentation. Patient-derived purified serum IgG was used to assess the breadth of HCV E1E2 binding and the neutralization activity of HCV pseudoparticles. The binding and neutralization activity results for two panels bearing viral envelope proteins representing either an intergenotype or an intragenotype 1 group were compared. We found that the HCV load was negatively associated with strong cross-genotypic E1E2 binding (P ؍ 0.03). Overall, we observed only a modest correlation between total E1E2 binding and neutralization ability. The breadth of intergenotype neutralization did not correlate with any clinical parameters; however, analysis of individuals with genotype 1 (gt1) HCV infection (n ؍ 20), using an intragenotype pseudoparticle panel, found a strong association between neutralization breadth and reduced liver fibrosis (P ؍ 0.006). A broad bNAb response in our cohort with chronic infection was associated with a single nucleotide polymorphism (SNP) in the HLA-DQB1 gene (P ؍ 0.038), as previously reported in a cohort with acute disease. Furthermore, the bNAbs in these individuals targeted more than one region of E2-neutralizing epitopes, as assessed through cross-competition of patient bNAbs with well-characterized E2 antibodies. We conclude that the bNAb responses in patients with chronic gt1 infection are associated with lower rates of fibrosis and host genetics may play a role in the ability to raise such responses. IMPORTANCEGlobally, there are 130 million to 150 million people with chronic HCV infection. Typically, the disease is progressive and is a major cause of severe liver cirrhosis and hepatocellular carcinoma. While it is known that neutralizing antibodies have a role in spontaneous clearance during acute infection, little is known about their role in chronic infection. In the present work, we investigated the antibody response in a cohort of chronically infected individuals and found that a broadly neutralizing antibody response is protective and is associated with reduced levels of liver fibrosis and cirrhosis. We also found an association between SNPs in class II HLA genes and the presence of a broadly neutralizing response, indicating that antigen presentation may be important for the production of HCV-neutralizing antibodies. H epatitis C virus (HCV) is a significant cause of liver morbidity and mortality worldwide (1). In the majority (75%) of those infected, the infection proceeds to a chronic infection (2). Symptomatic acute HCV infection is rare; therefore, HCV has the potential to spread undetected among those at risk. In countries with a high prevalence, a poor health care i...
Background: Hepatitis E virus (HEV) is the most common acute viral hepatitis inScotland. Little is known about the burden of morbidity and mortality, which can be high in chronic liver disease or immunocompromised states. Aims:To record the morbidity and mortality of HEV in Scotland. Methods:Demographic, clinical and laboratory data were collected retrospectively from all cases of HEV reported to virology departments across nine NHS health boards, Results: Five hundred and eleven cases were included (Mean age 62, 64% male). 58 (11%) cases had pre-existing cirrhosis and 110 (21%) had diabetes. Three hundred and three patients required admission (59%), totalling 2747 inpatient bed days.Seventeen (3.3%) HEV-related deaths were recorded. Factors that predicted mortality included haematological malignancy (OR 51.56, 95% CI 3.40-782.83, P = 0.005), cirrhosis (OR 41.85, 95% CI 2.85-594.16, P = 0.006), higher serum bilirubin (OR 1.01, 95% CI 1.01-1.02, P = 0.011) and chronic HEV infection (OR 0.02, 95% CI 0.02-0.28, P < 0.001). HEV infection affected 35 transplant patients of 106 total immunosuppressed patients (21%). Of these, 25 patients received Ribavirin therapy with a sustained virological remission of 76%. Thirty-five (6.7%) patients developed acute or acute-on-chronic liver failure with two requiring transplant. Thirty-seven (7.2%) patients reported neurological complications with 10 developing neuralgic amyotrophy, 6 Guillain-Barré and 2 encephalitis. Forty-four (8.6%) patients developed acute kidney injury. Conclusion:In Scotland, HEV causes a significant burden of inpatient admissions, organ failure and death. Cirrhosis and haematological malignancy are significant predictors of mortality. Neurological and renal complications occur in a significant minority. | 975WALLACE Et AL.
Chronic coinfection with hepatitis C virus (HCV) and hepatitis B virus (HBV) is associated with adverse liver outcomes. The clinical impact of previous HBV infection on liver disease in HCV infection is unknown. We aimed at determining any association of previous HBV infection with liver outcomes using antibodies to the hepatitis B core antigen (HBcAb) positivity as a marker of exposure. The Scottish Hepatitis C Clinical Database containing data for all patients attending HCV clinics in participating health boards was linked to the HBV diagnostic registry and mortality data from Information Services Division, Scotland. Survival analyses with competing risks were constructed for time from the first appointment to decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver-related mortality. Records of 8513 chronic HCV patients were included in the analyses (87 HBcAb positive and HBV surface antigen [HBsAg] positive, 1577 HBcAb positive and HBsAg negative, and 6849 HBcAb negative). Multivariate cause-specific proportional hazards models showed previous HBV infection (HBcAb positive and HBsAg negative) significantly increased the risks of decompensated cirrhosis (hazard ratio [HR]: 1.29, 95% CI: 1.01-1.65) and HCC (HR: 1.64, 95% CI: 1.09-2.49), but not liver-related death (HR: 1.02, 95% CI: 0.80-1.30). This is the largest study to date showing an association between previous HBV infection and certain adverse liver outcomes in HCV infection. Our analyses add significantly to evidence which suggests that HBV infection adversely affects liver health despite apparent clearance. This has important implications for HBV vaccination policy and indications for prioritization of HCV therapy.
SummaryInjection drug users uninfected by hepatitis C virus (HCV) despite likely repeated exposure through high‐risk behaviour are well documented. Factors preventing infection in these individuals are incompletely understood. Here, we looked for anti‐HCV‐envelope antibody responses in a cohort of repeatedly exposed but uninfected subjects. Forty‐two hepatitis C diagnostic antibody‐ and RNA‐negative injection drug users at high risk of exposure were studied and findings compared to healthy controls and cases with chronic HCV infection. Purified IgGs from sera were tested by ELISA for binding to genotype 1a and 3a envelope glycoproteins E1E2 with further testing for IgG and IgM reactivity against soluble E2. Virus‐neutralizing activity was assessed using an HCV pseudoparticle system. Uninfected subjects demonstrated significantly greater IgG and IgM reactivities to envelope glycoproteins than healthy controls with IgG from 6 individuals additionally showing significant neutralization. This study is the first to describe humoral immunological responses targeting the HCV envelope, important for viral neutralization, in exposed uninfected individuals. A subset of these cases also had evidence of viral neutralization via anti‐envelope antibodies. In addition to confirming viral exposure, the presence of specific anti‐envelope antibodies may be a factor that helps these individuals resist HCV infection.
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