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The role that broadly neutralizing antibodies (bNAbs) play in natural clearance of human hepatitis C virus (HCV) infection and the underlying mechanisms remain unknown. Here, we investigate the mechanism by which bNAbs, isolated from two humans who spontaneously cleared HCV infection, contribute to HCV control. Using viral gene sequences amplified from longitudinal plasma of the two subjects, we found that these bNAbs, which target the front layer of the HCV envelope protein E2, neutralized most autologous HCV strains. Acquisition of resistance to bNAbs by some autologous strains was accompanied by progressive loss of E2 protein function, and temporally associated with HCV clearance. These data demonstrate that bNAbs can mediate clearance of human HCV infection by neutralizing infecting strains and driving escaped viruses to an unfit state. These immunopathologic events distinguish HCV from HIV-1 and suggest that development of an HCV vaccine may be achievable.
Copyright © 2018 Elsevier Inc. All rights reserved.
Hepatitis C virus (HCV) vaccine efforts are hampered by the extensive genetic diversity of HCV envelope glycoproteins E1 and E2. Structures of broadly neutralizing antibodies (bNAbs) (e.g., HEPC3, HEPC74) isolated from individuals who spontaneously cleared HCV infection facilitate immunogen design to elicit antibodies against multiple HCV variants. However, challenges in expressing HCV glycoproteins previously limited bNAb-HCV structures to complexes with truncated E2 cores. Here we describe crystal structures of full-length E2 ectodomain complexes with HEPC3 and HEPC74, revealing lock-and-key antibody-antigen interactions, E2 regions (including a target of immunogen design) that were truncated or disordered in E2 cores, and an antibody CDRH3 disulfide motif that exhibits common interactions with a conserved epitope despite different bNAb-E2 binding orientations. The structures display unusual features relevant to common genetic signatures of HCV bNAbs and demonstrate extraordinary plasticity in antibody-antigen interactions. In addition, E2 variants that bind HEPC3/HEPC74-like germline precursors may represent candidate vaccine immunogens.
Copyright © 2018 Elsevier Inc. All rights reserved.
There is an urgent need for a vaccine to combat the hepatitis C virus (HCV) pandemic, and induction of broadly neutralizing monoclonal antibodies (bNAbs) against HCV is a major goal of vaccine development. Even within HCV genotype 1, no single bNAb effectively neutralizes all viral strains, so induction of multiple neutralizing monoclonal antibodies (NAbs) targeting distinct epitopes may be necessary for protective immunity. Therefore, identification of optimal NAb combinations and characterization of NAb interactions can guide vaccine development. We analyzed neutralization profiles of 12 human NAbs across diverse HCV strains, assigning the NAbs to two functionally distinct clusters. We then measured neutralizing breadth of 35 NAb combinations against genotype 1 isolates, with each combination including one NAb from each neutralization cluster. Many NAbs displayed complementary neutralizing breadth, forming combinations with greater neutralization across diverse strains than any individual bNAb. Remarkably, one of the most broadly neutralizing combinations of two NAbs, designated HEPC74/HEPC98, also displayed enhanced potency, with interactions matching the Bliss independence model, suggesting that these NAbs inhibit HCV infection through independent mechanisms. Subsequent experiments showed that HEPC74 primarily blocks HCV envelope protein binding to CD81, while HEPC98 primarily blocks binding to scavenger receptor B1 and heparan sulfate. Together, these data identify a critical vulnerability resulting from the reliance of HCV on multiple cell surface receptors, suggesting that vaccine induction of multiple NAbs with distinct neutralization profiles is likely to enhance the breadth and potency of the humoral immune response against HCV.
UNLABELLED - Chronic hepatitis B (CHB), chronic hepatitis C (CHC), and associated hepatocellular carcinoma (HCC) are characterized by cholesterol imbalance and dyslipidemia; however, the key regulatory drivers of these phenotypes are incompletely understood. Using gene expression microarrays and high-throughput sequencing of small RNAs, we performed integrative analysis of microRNA (miRNA) and gene expression in nonmalignant and matched cancer tissue samples from human subjects with CHB or CHC and HCC. We also carried out follow-up functional studies of specific miRNAs in a cell-based system. These studies led to four major findings. First, pathways affecting cholesterol homeostasis were among the most significantly overrepresented among genes dysregulated in chronic viral hepatitis and especially in tumor tissue. Second, for each disease state, specific miRNA signatures that included miRNAs not previously associated with chronic viral hepatitis, such as miR-1307 in CHC, were identified. Notably, a few miRNAs, including miR-27 and miR-224, were components of the miRNA signatures of all four disease states: CHB, CHC, CHB-associated HCC, and CHC-associated HCC. Third, using a statistical simulation method (miRHub) applied to the gene expression data, we identified candidate master miRNA regulators of pathways controlling cholesterol homeostasis in chronic viral hepatitis and HCC, including miR-21, miR-27, and miR-33. Last, we validated in human hepatoma cells that both miR-21 and miR-27 significantly repress cholesterol synthesis and that miR-27 does so in part through regulation of the gene that codes for the rate-limiting enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMGCR).
IMPORTANCE - Hepatitis B virus (HBV) and hepatitis C virus (HCV) are phylogenetically unrelated hepatotropic viruses that persistently infect hundreds of millions of people world-wide, often leading to chronic liver disease and hepatocellular carcinoma (HCC). Chronic hepatitis B (CHB), chronic hepatitis C (CHC), and associated HCC often lead to cholesterol imbalance and dyslipidemia. However, the regulatory mechanisms underlying the dysregulation of lipid pathways in these disease states are incompletely understood. MicroRNAs (miRNAs) have emerged as critical modulators of lipid homeostasis. Here we use a blend of genomic, molecular, and biochemical strategies to identify key miRNAs that drive the lipid phenotypes of chronic viral hepatitis and HCC. These findings provide a panoramic view of the miRNA landscape in chronic viral hepatitis, which could contribute to the development of novel and more-effective miRNA-based therapeutic strategies.
Copyright © 2015 Selitsky et al.
SETTING - Nine months of daily isoniazid (9H) and 3 months of once-weekly rifapentine plus isoniazid (3HP) are recommended treatments for latent tuberculous infection (LTBI). The risk profile for 3HP and the contribution of hepatitis C virus (HCV) infection to hepatotoxicity are unclear.
OBJECTIVES - To evaluate the hepatotoxicity risk associated with 3HP compared to 9H, and factors associated with hepatotoxicity.
DESIGN - Hepatotoxicity was defined as aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST >5 x ULN. We analyzed risk factors among adults who took at least 1 dose of their assigned treatment. A nested case-control study assessed the role of HCV.
RESULTS - Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors.
CONCLUSION - The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. HCV and elevated baseline AST were risk factors for hepatotoxicity. For persons with these risk factors, 3HP may be preferred.
BACKGROUND & AIMS - Genetic polymorphisms within the interferon lambda (IFN-λ) region are strongly associated with hepatitis C virus (HCV) clearance; the IFNL4-ΔG/TT (rs368234815) polymorphism, which controls the generation of IFN-λ4 protein, is more strongly associated with HCV clearance than rs12979860 (the 'IL28B variant'). An IFNL3 3' untranslated region polymorphism (rs4803217) has been proposed as a causal variant that may affect HCV clearance by altering IFNL3 mRNA stability.
METHODS - We compared IFNL4-ΔG/TT and rs4803217 for association with response to pegylated-IFN-α/ribavirin in the VIRAHEP-C and HALT-C trials, and spontaneous HCV clearance in the ALIVE, UHS and WIHS studies. Genotyping was performed with TaqMan assays. We compared differences in mean reduction in HCV RNA levels by genotype and haplotype. For HCV clearance, we calculated p-values comparing c-statistics for IFNL4-ΔG/TT and rs4803217 genotypes by a bootstrap approach.
RESULTS - Among European Americans, linkage disequilibrium between IFNL4-ΔG/TT and rs4803217 was strong (r(2)=0.89-0.99) and there were no significant differences between the variants. In African American (AA) individuals enrolled in VIRAHEP-C, HCV RNA at treatment day 28 was more strongly associated with IFNL4-ΔG/TT than rs4803217 (p=0.003); the IFNL4-ΔG:rs4803217-G haplotype, which includes the putatively favorable IFNL3 allele, was actually associated with the poorest day 28 response (p=0.03, comparison to IFNL4-ΔG:rs4803217-T haplotype). Among AA participants, associations were stronger for IFNL4-ΔG/TT than rs4803217 for undetectable HCV RNA at week 24 in Virahep-C (p=0.03) and week 20 in HALT-C (p=0.03), as well as for spontaneous HCV clearance (p=0.048).
CONCLUSION - IFNL4-ΔG/TT is the primary IFN-λ region polymorphism for impaired HCV clearance.
Published by Elsevier B.V.
BACKGROUND - HIV-infected individuals with a history of transmission through injection drug use (IDU) have poorer survival than other risk groups. The extent to which higher rates of hepatitis C (HCV) infection in IDU explain survival differences is unclear.
METHODS - Adults who started antiretroviral therapy between 2000 and 2009 in 16 European and North American cohorts with >70% complete data on HCV status were followed for 3 years. We estimated unadjusted and adjusted (for age, sex, baseline CD4 count and HIV-1 RNA, AIDS diagnosis before antiretroviral therapy, and stratified by cohort) mortality hazard ratios for IDU (versus non-IDU) and for HCV-infected (versus HCV uninfected).
RESULTS - Of 32,703 patients, 3374 (10%) were IDU; 4630 (14%) were HCV+; 1116 (3.4%) died. Mortality was higher in IDU compared with non-IDU [adjusted HR 2.71; 95% confidence interval (CI): 2.32 to 3.16] and in HCV+ compared with HCV- (adjusted HR 2.65; 95% CI: 2.31 to 3.04). The effect of IDU was substantially attenuated (adjusted HR 1.57; 95% CI: 1.27 to 1.94) after adjustment for HCV, while attenuation of the effect of HCV was less substantial (adjusted HR 2.04; 95% CI: 1.68 to 2.47) after adjustment for IDU. Both IDU and HCV were strongly associated with liver-related mortality (adjusted HR 10.89; 95% CI: 6.47 to 18.3 for IDU and adjusted HR 14.0; 95% CI: 8.05 to 24.5 for HCV) with greater attenuation of the effect of IDU (adjusted HR 2.43; 95% CI: 1.24 to 4.78) than for HCV (adjusted HR 7.97; 95% CI: 3.83 to 16.6). Rates of CNS, respiratory and violent deaths remained elevated in IDU after adjustment for HCV.
CONCLUSIONS - A substantial proportion of the excess mortality in HIV-infected IDU is explained by HCV coinfection. These findings underscore the potential impact on mortality of new treatments for HCV in HIV-infected people.
BACKGROUND - We hypothesized that nitazoxanide (NTZ) added to pegylated interferon alfa-2a (PEG-IFN) and weight-based ribavirin (WBR) would improve hepatitis C virus (HCV) virologic responses in HCV treatment-naïve HIV-1/HCV genotype 1 coinfected persons.
METHODS - Prospective, single-arm study in which subjects received 4-week lead-in (NTZ 500 mg twice daily) followed by 48 weeks of NTZ, PEG-IFN, and WBR. We compared the HCV virologic responses of these subjects to historical controls from the completed ACTG study A5178 who received PEG-IFN and WBR and had similar subject characteristics. Primary endpoints were early virologic response and complete early virologic response (EVR and cEVR).
RESULTS - Among 67 subjects (78% male; 48% Black; median age, 50 years), EVR was achieved in 65.7% (90% CI, 55.0%-75.3%), cEVR in 38.8% (28.8%-49.6%). and SVR in 32.8% (23.4%-43.5%). EVR was higher with NTZ (51.4% in A5178; P = .03), but the sustained virologic response (SVR) proportion was similar (27.3% in A5178; P = .24). In contrast to A5178, SVR was similar across IL28B genotypes. Overall, NTZ was safe and well-tolerated.
CONCLUSION - Whereas EVR proportion improved significantly in this pilot study, the addition of NTZ to PEG-IFN/WBR did not significantly improve SVR compared to historical controls. NTZ may be associated with an attenuation of the effect of IL28B on HCV treatment response.
BACKGROUND - The role of active hepatitis C virus (HCV) replication in chronic kidney disease (CKD) risk has not been clarified.
METHODS - We compared CKD incidence in a large cohort of HIV-infected subjects who were HCV seronegative, HCV viremic (detectable HCV RNA), or HCV aviremic (HCV seropositive, undetectable HCV RNA). Stages 3 and 5 CKD were defined according to standard criteria. Progressive CKD was defined as a sustained 25% glomerular filtration rate (GFR) decrease from baseline to a GFR < 60 mL/min/1.73 m2. We used Cox models to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
RESULTS - A total of 52 602 HCV seronegative, 9508 HCV viremic, and 913 HCV aviremic subjects were included. Compared with HCV seronegative subjects, HCV viremic subjects were at increased risk for stage 3 CKD (adjusted HR 1.36 [95% CI, 1.26, 1.46]), stage 5 CKD (1.95 [1.64, 2.31]), and progressive CKD (1.31 [1.19, 1.44]), while HCV aviremic subjects were also at increased risk for stage 3 CKD (1.19 [0.98, 1.45]), stage 5 CKD (1.69 [1.07, 2.65]), and progressive CKD (1.31 [1.02, 1.68]).
CONCLUSIONS - Compared with HIV-infected subjects who were HCV seronegative, both HCV viremic and HCV aviremic individuals were at increased risk for moderate and advanced CKD.