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Hepatitis C virus (HCV) is a serious and growing public health problem despite recent developments of antiviral therapeutics. To achieve global elimination of HCV, an effective cross-genotype vaccine is needed. The failure of previous vaccination trials to elicit an effective cross-reactive immune response demands better vaccine antigens to induce a potent cross-neutralizing response to improve vaccine efficacy. HCV E1 and E2 envelope (Env) glycoproteins are the main targets for neutralizing antibodies (nAbs), which aid in HCV clearance and protection. Therefore, a molecular-level understanding of the nAb responses against HCV is imperative for the rational design of cross-genotype vaccine antigens. Here we summarize the recent advances in structural studies of HCV Env and Env-nAb complexes and how they improve our understanding of immune recognition of HCV. We review the structural data defining HCV neutralization epitopes and conformational plasticity of the Env proteins, and the knowledge applicable to rational vaccine design.

Nearly 3 million people worldwide are coinfected with HIV and HCV. Affordable strategies for prevention are needed. We developed a novel vaccination regimen involving replication-defective and serologically distinct chimpanzee adenovirus (ChAd3, ChAd63) vector priming followed by modified vaccinia Ankara (MVA) boosts, for simultaneous delivery of HCV non-structural (NSmut) and HIV-1 conserved (HIVconsv) region immunogens. We conducted a phase I trial in which 33 healthy volunteers were sequentially enrolled and vaccinated via the intramuscular route as follows: 9 received ChAd3-NSmut [2.5 × 10 vp] and MVA-NSmut [2 × 10 pfu] at weeks 0 and 8, respectively; 8 received ChAdV63.HIVconsv [5 × 10 vp] and MVA.HIVconsv [2 × 10 pfu] at the same interval; 16 were co-primed with ChAd3-NSmut [2.5 × 10 vp] and ChAdV63.HIVconsv [5 × 10 vp] followed at week 8 by MVA-NSmut and MVA.HIVconsv [both 1 × 10 pfu]. Immunogenicity was assessed using peptide pools in ELISpot and intracellular cytokine assays. Vaccine-induced whole blood transcriptome changes were assessed by microarray analysis. All vaccines were well tolerated and no vaccine-related serious adverse events occurred. Co-administration of the prime-boost vaccine regimens induced high magnitude and broad T cell responses that were similar to those observed following immunization with either regimen alone. Median (interquartile range, IQR) peak responses to NSmut were 3,480 (2,728-4,464) and 3,405 (2,307-7,804) spot-forming cells (SFC)/10 PBMC for single and combined HCV vaccinations, respectively ( = 0.8). Median (IQR) peak responses to HIVconsv were 1,305 (1,095-4,967) and 1,005 (169-2,482) SFC/10 PBMC for single and combined HIV-1 vaccinations, respectively ( = 0.5). Responses were maintained above baseline to 34 weeks post-vaccination. Intracellular cytokine analysis indicated that the responding populations comprised polyfunctional CD4 and CD8 T cells. Canonical pathway analysis showed that in the single and combined vaccination groups, pathways associated with antiviral and innate immune responses were enriched for upregulated interferon-stimulated genes 24 h after priming and boosting vaccinations. Serologically distinct adenoviral vectors encoding HCV and HIV-1 immunogens can be safely co-administered without reducing the immunogenicity of either vaccine. This provides a novel strategy for targeting these viruses simultaneously and for other pathogens that affect the same populations. https://clinicaltrials.gov, identifier: NCT02362217.

BackgroundOur recent study indicated the possible presence of detectable hepatitis C virus antigens (HCV-Ags) after denaturation of sera with resolved HCV (R-HCV) infection. The present study determined and characterized persistent HCV-Ags-specific immune complexes (ICs) in these patients.MethodsSixty-eight sera with R-HCV and 34 with viremic HCV (V-HCV) infection were tested for free and IC-bound HCV-Ags using HCV-Ags enzyme immunoassay (EIA), the presence of HCV-Ags-specific ICs by immunoprecipitation and Western blot (IP–WB), HCV ICs containing HCV virions using IP and HCV RNA RT-PCR, and correlation of HCV ICs with clinical presentation in these patients.ResultsUsing HCV-Ags EIA, we found 57.4% of sera with R-HCV infection were tested positive for bound, but not free HCV-Ags. Using pooled or individual anti-HCV E1/E2, cAg, NS3, NS4b, and/or NS5a to precipitate HCV-specific-Ags, we confirmed persistent HCV-Ags ICs specific to various HCV structural and non-structural proteins not only in V-HCV infection, but also in R-HCV infection. Using IP and HCV RNA PCR, we then confirmed the presence of HCV virions within circulating ICs in V-HCV, but not in R-HCV sera. Multivariable analysis indicated significant and independent associations of persistent circulating HCV-Ags-specific ICs with both age and the presence of cirrhosis in patients with R-HCV infection.ConclusionsVarious HCV-Ag-specific ICs, but not virions, persist in 57.4% of patients who had spontaneous or treatment-induced HCV clearance for 6 months to 20 years. These findings enriched our knowledge on HCV pathogenesis and support further study on its long-term clinical relevance, such as extrahepatic manifestation, transfusion medicine, and hepatocarcinogenesis.

We previously identified that miR-130a downregulates HCV replication through two independent pathways: restoration of host immune responses and regulation of pyruvate metabolism. In this study, we further sought to explore host antiviral target genes regulated by miR-130a. We performed a RT² Profiler™ PCR array to identify the host antiviral genes regulated by miR-130a. The putative binding sites between miR-130a and its downregulated genes were predicted by miRanda. miR-130a and predicted target genes were over-expressed or knocked down by siRNA or CRISPR/Cas9 gRNA. Selected gene mRNAs and their proteins, together with HCV replication in JFH1 HCV-infected Huh7.5.1 cells were monitored by qRT-PCR and Western blot. We identified 32 genes that were significantly differentially expressed more than 1.5-fold following miR-130a overexpression, 28 of which were upregulated and 4 downregulated. We found that ATG5, a target gene for miR-130a, significantly upregulated HCV replication and downregulated interferon stimulated gene expression. miR-130a downregulated ATG5 expression and its conjugation complex with ATG12. ATG5 and ATG5-ATG12 complex affected interferon stimulated gene (ISG) such as MX1 and OAS3 expression and subsequently HCV replication. We concluded that miR-130a regulates host antiviral response and HCV replication through targeting ATG5 via the ATG5-dependent autophagy pathway.

INTRODUCTION : le virus de l'hépatite C (VHC) a plusieurs manifestations extra hépatiques parmi lesquelles la cryoglubulinémie. La cryoglobulinémie se définit par la présence anormale dans le sang d'une ou plusieurs protéines (cryoglobuline) pouvant précipiter au froid.Méthodes: nous avons mené une étude transversale et analytique dans le service du laboratoire de biologie et l'unité d'hépatologie de l'Hôpital Général de Douala (HGD) pendant une durée de 6 mois. Etaient inclus dans le travail tous les patients acceptant de participer et porteurs d'un anticorps anti VHC avec ou sans traitement. Les cryoglobulines étaient recherchés par la méthode de Biuret et la classification était réalisée par une immunoélectrophorèse de Brouet. Une analyse multivariée a été réalisée, des facteurs de confusion tels que l'âge, le sexe et la durée après dépistage du VHC ont été ajustés.Résultats: nous avons inclus 116 patients. L'âge moyen était de 58,47 ± 9,95 ans. Le sexe masculin représentait 50,86% des cas. L'arthralgie était présente dans 69,80% des cas. La cryoglubiline était présente chez 63,80% des cas. Apres ajustement, le sexe féminin (ORa =2,18; IC à 95% [0,97-4, 90]; p= 0,059), l'asthénie seule (ORa =2,45; IC à 95% [1,04-5,80]; p= 0,041), l'asthénie couplée à l'arthralgie (ORa =2,84; IC à 95% [1,13-7, 10]; p= 0,026) et la présence de l'ARN du VHC (ORa =2,84; IC à 95% [1,13-7, 10]; p= 0,028) étaient des facteurs indépendamment associés à la présence de cryoglobuline.Conclusion: la prévalence de la cryoglobubine est élevée chez les patients porteurs de l'nAc anti VHC à l'HGD. Elle est recherchée par les méthodes biologiques simples. La recherche de cryoglobuline chez les patients porteurs du VHC est essentielle dans un pays à ressource limité.

Abstract Objectives To study the pathologic spectrum of kidney diseases in patients with hepatitis C virus infection (HCV+). Methods Native kidney biopsy specimens in HCV+ patients were reviewed. Results A total of 9,836 native kidney biopsy specimens were evaluated from January 2007 to December 2016, of which 273 (2.8%) were from HCV+ patients, and of these, 115 (42.1%) had diagnoses consistent with HCV-associated glomerulonephritis (GN). Non–HCV-associated kidney diseases comprised most diagnoses (158 cases, 57.9%) including non–immune complex–mediated kidney diseases (127 cases, 46.5%) and other immune complex–mediated glomerular diseases (31 cases, 11.4%). Forty-one (40.6%) patients had HCV-associated GN among 101 HCV+ patients from 2007 to 2011 vs 74 (43.0%) patients with HCV-associated GN among 172 HCV+ patients from 2012 to 2016. HCV-associated GN showed five morphologic patterns: focal proliferative (5.2%), diffuse mesangial proliferative (50.4%), diffuse membranoproliferative (28.7%), proliferative GN with crescentic lesions (7.8%), and membranous patterns (7.8%). Conclusions We found a spectrum of pathologic changes in renal biopsy specimens of HCV+ patients, with most having diseases unrelated to HCV infection, HCV-associated GN showing five morphologic patterns, and availability of effective HCV antiviral therapy not yet resulting in major changes in the spectrum of kidney diseases in these patients.

Approximately 12% of human cancers worldwide are associated with infectious agents, which are classified by the International Agency for Research on Cancer (IARC) as Group 1 within the agents that are carcinogenic to humans. Most of these agents are viruses. Group 1 oncogenic viruses include hepatitis C virus, hepatitis B virus (HBV), human T-cell lymphotropic virus type 1, Epstein-Barr virus, Kaposi sarcoma-associated herpesvirus, human immunodeficiency virus-1 and high-risk human papillomaviruses (HPVs). In addition, some human polyomaviruses are suspected of inducing cancer prevalently in hosts with impaired immune responses. Merkel cell polyomavirus has been associated with Merkel cell carcinoma and included by the IARC in Group 2A (i.e., probably carcinogenic to humans). Linking viruses to human cancers has allowed for the development of diagnostic, prophylactic and therapeutic measures. Vaccination significantly reduced tumours induced by two oncogenic viruses as follows: HBV and HPV. Herein, we focus on mucosal alpha HPVs, which are responsible for the highest number of cancer cases due to tumour viruses and against which effective prevention strategies have been developed to reduce the global burden of HPV-related cancers.

Objective: To determine the efficacy of dual (sofosbuvir and ribavirin) and triple therapy (sofosbuvir ribavirinpegylated interferon) for treatment of hepatitis C. Study Design: Comparative cross sectional study. Place and Duration of Study: Department of Medicine, Combined Military Hospital, Lahore, from Nov 2014 to Mar 2017. Methodology: A total of 182 consecutive patients with age ≥18 years and positive HCV RNA by polymerase chain reaction were included, while patients with haemoglobin of <10 g/dl, albumin <2 g/dl, platelet count of <100/uL, creatinine clearance of <60 mL/min or liver disease caused by non-hepatitis C related causes were excluded from study. Results: Total 129 (70.8%) were treated with dual and 53 (29.1%) with triple therapy. Amongst patients with genotype 3 (158/182), the overall sustained virological response at 12 weeks (SVR 12) was 94.4% in patients with dual therapy while it was 97.3% with triple therapy. In non-cirrhotic patients it was 95% in treatment naïve and 100% in treatment experienced group. While in cirrhotic patients with genotype 3, SVR 12 with dual therapy was 83.3% (p=0.331) and 88.9% in treatment naïve and treatment experienced patients respectively, while it was 100% in both groups with triple therapy. SVR 12 for genotype 1 (21/182) was 100%, both for dual as well as for triple therapy. Haematological side effects dominated the clinical picture with 11.5% suffering from anaemia. Conclusion: Both dual and triple therapy were effective in patients with hepatitis C with acceptable level of side effects, genotype 3 being the most predominant genotype.

Replication of the hepatitis C virus (HCV) strongly relies on various lipid metabolic processes in different steps of the viral life cycle. In general, HCV changes the cells’ lipidomic profile by differentially regulating key pathways of lipid synthesis, remodeling, and utilization. In this review, we sum up the latest data mainly from the past five years, emphasizing the role of lipids in HCV RNA replication, assembly, and egress. In detail, we highlight changes in the fatty acid content as well as alterations of the membrane lipid composition during replication vesicle formation. We address the role of lipid droplets as a lipid provider during replication and as an essential hub for HCV assembly. Finally, we depict different ideas of HCV maturation and egress including lipoprotein association and potential secretory routes.

Viral hepatitis is a global health concern mostly caused by hepatitis B virus (HBV) and hepatitis C virus (HCV). The late diagnosis and delayed treatment of HBV and HCV infections can cause irreversible liver damage and the occurrence of cirrhosis and hepatocellular carcinoma. Detecting the presence and activity of HBV and HCV is the cornerstone of the diagnosis and management of related diseases. However, the traditional method shows limitations. The utilization of nanomaterials has been of great significance in the advancement of virus detection technologies due to their unique mechanical, electrical, and optical properties. Here, we categorized and illustrated the novel approaches used for the diagnosis of HBV and HCV.