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3642 KiB

Open AccessArticle

A Protease Inhibitor with Induction Therapy with Natural Interferon-β in Patients with HCV Genotype 1b Infection

by Yutaka Kishida, Naohiko Imaizumi, Hirohisa Tanimura, Shinichiro Kashiwamura and Toru Kashiwagi

Int. J. Mol. Sci. 2016, 17(3), 350; https://doi.org/10.3390/ijms17030350 - 9 Mar 2016

Cited by 2 | Viewed by 4791

Abstract

The restoration of innate immune responses has potential as a novel therapeutic strategy for chronic hepatitis C (CHC). We compared the efficacy and safety of induction therapy (IT) with natural interferon-β (n-IFN-β) followed by pegylated-IFN-α/ribavirin (PR) alone (group A, n = 30) and [...] Read more.

The restoration of innate immune responses has potential as a novel therapeutic strategy for chronic hepatitis C (CHC). We compared the efficacy and safety of induction therapy (IT) with natural interferon-β (n-IFN-β) followed by pegylated-IFN-α/ribavirin (PR) alone (group A, n = 30) and IT with a protease inhibitor (PI) (simeprevir or vaniprevir)/PR (group B, n = 13) in CHC patients with genotype 1b and high viral loads. During IT with nIFN-β, virologic response rates in group A and group B were 10% and 8% (p = 0.6792) at week 4, 30% and 16% (p = 0.6989) at week 12 and 47% and 20% (p = 0.0887) at week 24 respectively. During and after the treatment with PR alone or PI/PR, virologic response rates in groups A and B were 50% and 82% (p = 0.01535) at week 4, 53% and 91% (p = 0.006745) at week 8, 57% and 91% (p = 0.001126) at week 12, 57% and 100% (p < 0.001845) at the end of the treatment and 57% and 80% (p < 0.005166) after treatment cessation. IT with PI/PR linked to the restoration of innate immune response was tolerated well, overcame virological breakthrough, enhanced early virologic responses, and resulted in a sustained virologic response in difficult-to-treat CHC patients. IT with PI/PR is beneficial for treating difficult-to-treat CHC patients. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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955 KiB

Open AccessArticle

Effect of Hepatitis C Virus Genotype 1b Core and NS5A Mutations on Response to Peginterferon Plus Ribavirin Combination Therapy

by Shingo Nakamoto, Fumio Imazeki, Makoto Arai, Shin Yasui, Masato Nakamura, Yuki Haga, Reina Sasaki, Tatsuo Kanda, Hiroshi Shirasawa and Osamu Yokosuka

Int. J. Mol. Sci. 2015, 16(9), 21177-21190; https://doi.org/10.3390/ijms160921177 - 7 Sep 2015

Cited by 2 | Viewed by 5508

Abstract

We examined whether hepatitis C virus (HCV) genotype 1b core- and NS5A-region mutations are associated with response to peginterferon α-2b plus ribavirin combination therapy. A total of 103 patients with high HCV genotype 1b viral loads (≥100 KIU/mL) were treated with the combination [...] Read more.

We examined whether hepatitis C virus (HCV) genotype 1b core- and NS5A-region mutations are associated with response to peginterferon α-2b plus ribavirin combination therapy. A total of 103 patients with high HCV genotype 1b viral loads (≥100 KIU/mL) were treated with the combination therapy. Pretreatment mutations in the core region and interferon sensitivity determining region (ISDR) in the NS5A region were analyzed. In univariate analysis, arginine and leucine at positions 70 and 91 in the core region, defined as double wild (DW)-type, were associated with early virologic response (p = 0.002), sustained virologic response (SVR) (p = 0.004), and non-response (p = 0.005). Non-threonine at position 110 was associated with SVR (p = 0.004). Multivariate analysis showed the following pretreatment predictors of SVR: hemoglobin level ≥ 14 g/dL (odds ratio (OR) 6.2, p = 0.04); platelet count ≥ 14 × 10⁴/mm³ (OR 5.2, p = 0.04); aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio < 0.9 (OR 6.17, p = 0.009); DW-type (OR 6.8, p = 0.02); non-threonine at position 110 (OR 14.5, p = 0.03); and ≥2 mutations in the ISDR (OR 12.3, p = 0.02). Patients with non-DW-type, non-threonine at position 110, and <2 ISDR mutations showed significantly lower SVR rates than others (11/45 (24.4%) vs. 27/37 (73.0%), respectively; p < 0.001). SVR can be predicted through core and NS5A region mutations and host factors like hemoglobin, platelet count, and AST/ALT ratio in HCV genotype 1b-infected patients treated with peginterferon and ribavirin combination therapy. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Figure 1

Figure 1
Specific amino acid patterns in the core region of hepatitis C genotype 1b patients. At 14 of 191 positions, the most prevalent (wild-type) amino acid accounted for 50%–95% of the 103 sequences (A); The amino acid mutation rates of these positions between early virologic response (EVR) and non-EVR patients (B); and those between sustained virologic response (SVR) and non-SVR patients (C); p value is shown in the positions with significant difference in amino acid pattern between both groups; AA, amino acid. Full article ">Figure 1 Cont.
Specific amino acid patterns in the core region of hepatitis C genotype 1b patients. At 14 of 191 positions, the most prevalent (wild-type) amino acid accounted for 50%–95% of the 103 sequences (A); The amino acid mutation rates of these positions between early virologic response (EVR) and non-EVR patients (B); and those between sustained virologic response (SVR) and non-SVR patients (C); p value is shown in the positions with significant difference in amino acid pattern between both groups; AA, amino acid. Full article ">Figure 2
Viral kinetics according to amino acid mutations in the core region of hepatitis C genotype 1b patients treated with peginterferon plus ribavirin combination therapy. The mean decline in hepatitis C virus (HCV) RNA levels from baseline to weeks 4 and 12 during therapy are plotted. Vertical bars with terminal horizontal bars express standard deviation. Double wild (DW)-type: arginine and leucine at positions 70 and 91; non-DW-type: the other patterns of amino acids. Full article ">Figure 3
The proportion of patients with double wild (DW)-type or non-DW-type in the core region according to fibrosis staging. Patients showed a decreasing trend for the proportion of DW-type amino acid according to fibrosis stage (p = 0.01). DW-type: arginine and leucine at positions 70 and 91 in the core region; non-DW-type: the other patterns of amino acids. Full article ">

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Open AccessArticle

Impact of Chronic Hepatitis C Virus Genotype 1b Infection on Triglyceride Concentration in Serum Lipoprotein Fractions

by Tomohisa Nagano, Nobuyoshi Seki, Yoichi Tomita, Tomonori Sugita, Yuta Aida, Munenori Itagaki, Satoshi Sutoh, Hiroshi Abe, Akihito Tsubota and Yoshio Aizawa

Int. J. Mol. Sci. 2015, 16(9), 20576-20594; https://doi.org/10.3390/ijms160920576 - 31 Aug 2015

Cited by 14 | Viewed by 6609

Abstract

Reduced low-density lipoprotein (LDL) cholesterol level is a characteristic feature of dyslipidemia in chronic hepatitis C virus (HCV) infection. However, abnormality in serum triglyceride (TG) has not been fully investigated. To clarify the impact of HCV genotype 1b (G1b) infection and advanced fibrosis [...] Read more.

Reduced low-density lipoprotein (LDL) cholesterol level is a characteristic feature of dyslipidemia in chronic hepatitis C virus (HCV) infection. However, abnormality in serum triglyceride (TG) has not been fully investigated. To clarify the impact of HCV genotype 1b (G1b) infection and advanced fibrosis on serum TG profiles, TG concentrations in lipoprotein fractions were examined in fasting sera from 185 subjects with active or cleared HCV infection by high-performance liquid chromatography. Serum lipoproteins were fractionated into four classes: chylomicron, very low-density lipoprotein (VLDL), LDL, and high-density lipoprotein (HDL). Then, the significance of HCV G1b infection on TG levels in each lipoprotein fraction was determined using multiple regression models. We found that active HCV G1b infection was positively associated with high HDL-TG levels and low VLDL-TG levels, independent of other factors included in the regression model. In VLDL sub-fractions, active HCV infection was only found to be associated with low levels of large VLDL-TG. Similarly, advanced liver fibrosis in chronic HCV G1b infection was associated with high levels of LDL-TG, HDL-TG, and small VLDL-TG, independent of other clinical factors. These findings indicate that active HCV G1b infection and advanced fibrosis are closely associated with abnormal serum TG profiles. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
Comparison of triglyceride (TG) concentrations in lipoprotein sub-fractions between active HCV and SVR groups. Serum lipoprotein was fractionated by HPLC into 20 fractions according to the particle size, and the concentration of TG in each fraction was measured using an online detection system (Skylight Biotech, Inc., Akita, Japan). The fraction number and the mean particle size are shown at the bottom of the image (* p < 0.05; ** p < 0.01; *** p < 0.001). Full article ">Figure 2
Comparison of TG concentrations in the four major classes of serum lipoproteins between active HCV and SVR groups. (** p < 0.01; *** p < 0.001). Full article ">Figure 3
Comparison of the distribution of TG levels in the three VLDL sub-fractions for active HCV and SVR groups (* p < 0.05; *** p < 0.001). Full article ">Figure 4
Comparison of TG concentrations in lipoprotein sub-fractions between patients with advanced fibrosis and those with mild-moderate fibrosis. Serum lipoprotein was fractionated by HPLC into 20 fractions according to the particle size, and the concentration of TG in each fraction was measured using an online detection system (Skylight Biotech, Inc., Akita, Japan). The fraction number and the mean particle size of each fraction are presented at the bottom of the image (* p < 0.05; ** p < 0.01). Full article ">Figure 5
Comparison of the distribution of TG in the four major classes of serum lipoproteins between patients with advanced fibrosis and those with mild-moderate fibrosis (Adv, advanced; Mod, Moderate; * p < 0.05). Full article ">Figure 6
Comparison of the distribution of TG in VLDL sub-fractions between patients with advanced fibrosis and those with mild-moderate fibrosis (Adv; advanced, Mod; moderate, * p < 0.05; ** p < 0.01). Full article ">

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Open AccessArticle

Identification of Hydroxyanthraquinones as Novel Inhibitors of Hepatitis C Virus NS3 Helicase

by Atsushi Furuta, Masayoshi Tsubuki, Miduki Endoh, Tatsuki Miyamoto, Junichi Tanaka, Kazi Abdus Salam, Nobuyoshi Akimitsu, Hidenori Tani, Atsuya Yamashita, Kohji Moriishi, Masamichi Nakakoshi, Yuji Sekiguchi, Satoshi Tsuneda and Naohiro Noda

Int. J. Mol. Sci. 2015, 16(8), 18439-18453; https://doi.org/10.3390/ijms160818439 - 7 Aug 2015

Cited by 22 | Viewed by 7085

Abstract

Hepatitis C virus (HCV) is an important etiological agent of severe liver diseases, including cirrhosis and hepatocellular carcinoma. The HCV genome encodes nonstructural protein 3 (NS3) helicase, which is a potential anti-HCV drug target because its enzymatic activity is essential for viral replication. [...] Read more.

Hepatitis C virus (HCV) is an important etiological agent of severe liver diseases, including cirrhosis and hepatocellular carcinoma. The HCV genome encodes nonstructural protein 3 (NS3) helicase, which is a potential anti-HCV drug target because its enzymatic activity is essential for viral replication. Some anthracyclines are known to be NS3 helicase inhibitors and have a hydroxyanthraquinone moiety in their structures; mitoxantrone, a hydroxyanthraquinone analogue, is also known to inhibit NS3 helicase. Therefore, we hypothesized that the hydroxyanthraquinone moiety alone could also inhibit NS3 helicase. Here, we performed a structure–activity relationship study on a series of hydroxyanthraquinones by using a fluorescence-based helicase assay. Hydroxyanthraquinones inhibited NS3 helicase with IC₅₀ values in the micromolar range. The inhibitory activity varied depending on the number and position of the phenolic hydroxyl groups, and among different hydroxyanthraquinones examined, 1,4,5,8-tetrahydroxyanthraquinone strongly inhibited NS3 helicase with an IC₅₀ value of 6 µM. Furthermore, hypericin and sennidin A, which both have two hydroxyanthraquinone-like moieties, were found to exert even stronger inhibition with IC₅₀ values of 3 and 0.8 µM, respectively. These results indicate that the hydroxyanthraquinone moiety can inhibit NS3 helicase and suggest that several key chemical structures are important for the inhibition. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Figure 1
Structures of hydroxyanthraquinones and their IC50 values for NS3 helicase inhibition. The IC50 values were obtained from inhibition curves (<a href="#app1-ijms-16-18439" class="html-app">Figure S1</a>). The data in the inhibition curves are presented as mean ± standard deviation (SD) of three replicates using the fluorescence helicase assay. The NS3 helicase activities of samples containing inhibitor were calculated relative to control samples, containing DMSO vehicle instead of inhibitor. Full article ">Figure 2
Inhibition curves of (A) hypericin and (B) sennidin A generated using the fluorescence helicase assay. The NS3 helicase activities of samples containing inhibitor were calculated relative to control samples containing DMSO vehicle instead of inhibitor. The data are presented as mean ± standard deviation of three replicates. Full article ">Figure 3
Effect of hypericin on NS3 ATPase activity. Activity was demonstrated by autoradiography of an ATPase assay using [γ-32P]ATP. Lane 1 contains the control reaction without NS3; Lanes 2–9 show the ATP hydrolysis reaction with poly(U) RNA at increasing concentrations (0–100 μM) of hypericin. Full article ">Figure 4
Effect of hypericin on NS3 RNA-binding activity. Activity was assessed by autoradiography of a gel mobility-shift assay using 32P-labeled ssRNA. Lanes 1 and 2 contain control reactions with heat-denatured ssRNA and 300 nM BSA (instead of NS3), respectively; Lanes 3–10 show the RNA-binding reaction with increasing concentrations (0–100 μM) of hypericin. Full article ">

697 KiB

Open AccessArticle

Human Leukocyte Antigen Class II Alleles Are Associated with Hepatitis C Virus Natural Susceptibility in the Chinese Population

by Ming Yue, Ke Xu, Meng-Ping Wu, Ya-Ping Han, Peng Huang, Zhi-Hang Peng, Jie Wang, Jing Su, Rong-Bin Yu, Jun Li and Yun Zhang

Int. J. Mol. Sci. 2015, 16(8), 16792-16805; https://doi.org/10.3390/ijms160816792 - 23 Jul 2015

Cited by 9 | Viewed by 5109

Abstract

Human leukocyte antigen (HLA) class II molecule influences host antigen presentation and anti-viral immune response. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) within HLA class II gene were associated with different clinical outcomes of hepatitis C virus [...] Read more.

Human leukocyte antigen (HLA) class II molecule influences host antigen presentation and anti-viral immune response. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) within HLA class II gene were associated with different clinical outcomes of hepatitis C virus (HCV) infection. Three HLA class II SNPs (rs3077, rs2395309 and rs2856718) were genotyped by TaqMan assay among Chinese population, including 350 persistent HCV infection patients, 194 spontaneous viral clearance subjects and 973 HCV-uninfected control subjects. After logistic regression analysis, the results indicated that the rs2856718 TC genotype was significantly associated with the protective effect of the HCV natural susceptibility (adjusted OR: 0.712, 95% CI: 0.554–0.914) when compared with reference TT genotype, and this remained significant after false discovery rate (FDR) correction (p = 0.024). Moreover, the protective effect of rs2856718 was observed in dominant genetic models (adjusted OR: 0.726, 95% CI: 0.574–0.920), and this remained significant after FDR correction (p = 0.024). In stratified analysis, a significant decreased risk was found in rs2856718C allele in the male subgroup (adjusted OR: 0.778, 95% CI: 0.627–0.966) and hemodialysis subgroup (adjusted OR: 0.713, 95% CI: 0.552–0.921). Our results indicated that the genetic variations of rs2856718 within the HLA-DQ gene are associated with the natural susceptibility to HCV infection among the Chinese population. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Open AccessArticle

Skeletal Muscle Depletion Predicts the Prognosis of Patients with Hepatocellular Carcinoma Treated with Sorafenib

by Kenji Imai, Koji Takai, Tatsunori Hanai, Takayasu Ideta, Tsuneyuki Miyazaki, Takahiro Kochi, Atsushi Suetsugu, Makoto Shiraki and Masahito Shimizu

Int. J. Mol. Sci. 2015, 16(5), 9612-9624; https://doi.org/10.3390/ijms16059612 - 28 Apr 2015

Cited by 59 | Viewed by 6138

Abstract

The aim of this study was to determine whether skeletal muscle depletion predicts the prognosis of patients with hepatocellular carcinoma (HCC) that is being treated with sorafenib. We evaluated 40 consecutive HCC patients who received sorafenib treatment. The skeletal muscle cross-sectional area was [...] Read more.

The aim of this study was to determine whether skeletal muscle depletion predicts the prognosis of patients with hepatocellular carcinoma (HCC) that is being treated with sorafenib. We evaluated 40 consecutive HCC patients who received sorafenib treatment. The skeletal muscle cross-sectional area was measured by computed tomography at the third lumbar vertebra (L3), from which the L3 skeletal muscle index (L3 SMI) was obtained. The factors contributing to overall survival, sorafenib dose reduction, and discontinuation of sorafenib were analyzed using the Cox proportional hazards model. L3 SMI (p = 0.020) and log (α-fetoprotein (AFP)) (p = 0.010) were identified as independent prognostic factors in HCC patients treated with sorafenib. The initial dose of sorafenib (p = 0.008) was an independent risk factor for sorafenib dose reduction, and log (AFP) (p = 0.008) was the only significant risk factor for the discontinuation of this drug. L3 SMI was not a risk factor for either dose reduction (p = 0.423) or the discontinuation (p = 0.132) of sorafenib. A multiple linear regression analysis determined the following relationship between skeletal muscle mass (assessed as L3 SMI) and the explanatory factors: L3 SMI = −0.1896 × (Age) − 10.3441 × (Child-Pugh score) − 9.3922 × (log (AFP)) + 1.6139 × (log (AFP)) × (Child-Pugh score) + 112.9166. Skeletal muscle depletion is inversely associated with age, Child-Pugh score, and log (AFP). Moreover, it is an independent prognostic factor for HCC patients treated with sorafenib. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Open AccessArticle

Elevated Levels of Endocannabinoids in Chronic Hepatitis C May Modulate Cellular Immune Response and Hepatic Stellate Cell Activation

by Eleonora Patsenker, Philip Sachse, Andrea Chicca, María Salomé Gachet, Vreni Schneider, Johan Mattsson, Christian Lanz, Mathias Worni, Andrea De Gottardi, Mariam Semmo, Jochen Hampe, Clemens Schafmayer, Rudolf Brenneisen, Jürg Gertsch, Felix Stickel and Nasser Semmo

Int. J. Mol. Sci. 2015, 16(4), 7057-7076; https://doi.org/10.3390/ijms16047057 - 27 Mar 2015

Cited by 34 | Viewed by 7685

Abstract

The endocannabinoid (EC) system is implicated in many chronic liver diseases, including hepatitis C viral (HCV) infection. Cannabis consumption is associated with fibrosis progression in patients with chronic hepatitis C (CHC), however, the role of ECs in the development of CHC has never [...] Read more.

The endocannabinoid (EC) system is implicated in many chronic liver diseases, including hepatitis C viral (HCV) infection. Cannabis consumption is associated with fibrosis progression in patients with chronic hepatitis C (CHC), however, the role of ECs in the development of CHC has never been explored. To study this question, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) were quantified in samples of HCV patients and healthy controls by gas and liquid chromatography mass spectrometry. Fatty acid amide hydrolase (FAAH) and monoaclyglycerol lipase (MAGL) activity was assessed by [³H]AEA and [³H]2-AG hydrolysis, respectively. Gene expression and cytokine release were assayed by TaqMan PCR and ELISpot, respectively. AEA and 2-AG levels were increased in plasma of HCV patients, but not in liver tissues. Hepatic FAAH and MAGL activity was not changed. In peripheral blood mononuclear cells (PBMC), ECs inhibited IFN-γ, TNF-α, and IL-2 secretion. Inhibition of IL-2 by endogenous AEA was stronger in PBMC from HCV patients. In hepatocytes, 2-AG induced the expression of IL-6, -17A, -32 and COX-2, and enhanced activation of hepatic stellate cells (HSC) co-cultivated with PBMC from subjects with CHC. In conclusion, ECs are increased in plasma of patients with CHC and might reveal immunosuppressive and profibrogenic effects. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Figure 1
Endocannabinoid (ECs) and related fatty acid amides expression in hepatitis C. (A) Levels of ECs in plasma from patients with chronic hepatitis C (CHC) (n = 57) and healthy controls (n = 25); (B) levels of ECs, fatty acids amides and cortisol in control (n = 9) and hepatitis C virus (HCV)-infected (n = 17) liver tissues. * p = 0.0389 vs. control. Full article ">Figure 1 Cont.
Endocannabinoid (ECs) and related fatty acid amides expression in hepatitis C. (A) Levels of ECs in plasma from patients with chronic hepatitis C (CHC) (n = 57) and healthy controls (n = 25); (B) levels of ECs, fatty acids amides and cortisol in control (n = 9) and hepatitis C virus (HCV)-infected (n = 17) liver tissues. * p = 0.0389 vs. control. Full article ">Figure 2
Fatty acid amide hydrolase (FAAH) and monoaclyglycerol lipase (MAGL) mRNA and activity in CHC patients and healthy controls. (A) FAAH mRNA and MAGL mRNA in liver biopsies from CHC patients and control livers; (B) FAAH mRNA and MAGL mRNA in PBMC from CHC patients and healthy controls; (C) FAAH and MAGL enzymatic activity in liver biopsies from CHC patients and control livers. ns—not significant. Full article ">Figure 3
Internal regulation of the EC system by arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG). Cannabinoid receptors CB1, CB2, FAAH and MAGL mRNA expression in peripheral blood mononuclear cells (PBMC) by AEA (2.5 µM) and 2-AG (20 µM) was measured by TaqMan PCR and normalized to 18S RNA. * p < 0.05 vs. untreated control. Full article ">Figure 4
Inflammatory cytokines expression after EC treatment in PBMC. IFN-γ, TNF-α, IL-2 and IL-10 mRNA (A) and protein secretion (B) in phytohaemagglutinin (PHA)-stimulated PBMC isolated from healthy controls and HCV patients (n ≥ 10 each group); (C) IL-2 production after FAAH inhibition with PF-622 (1 µM). Results are expressed as arbitrary units or spot-forming cells (SFC) per 1 × 106 cells. * p < 0.05; ** p < 0.005; *** p < 0.0005 vs. corresponding controls. Full article ">Figure 4 Cont.
Inflammatory cytokines expression after EC treatment in PBMC. IFN-γ, TNF-α, IL-2 and IL-10 mRNA (A) and protein secretion (B) in phytohaemagglutinin (PHA)-stimulated PBMC isolated from healthy controls and HCV patients (n ≥ 10 each group); (C) IL-2 production after FAAH inhibition with PF-622 (1 µM). Results are expressed as arbitrary units or spot-forming cells (SFC) per 1 × 106 cells. * p < 0.05; ** p < 0.005; *** p < 0.0005 vs. corresponding controls. Full article ">Figure 5
AEA suppresses HCV-induced IFN-γ release in PBMC. (A) IFN-γ production in PBMC (n = 6) by HCV peptide pools (5 µg/mL) and 2.5 µM AEA. Results are expressed as spot-forming cells (SFC) per 1 × 106 cells; (B) FAAH, MAGL, CB1 and CB2 mRNA in PBMC by the NS3 HCV pool. * p < 0.05 vs. corresponding non-treated control. Full article ">Figure 6
ECs affect inflammatory and fibrogenic hepatic cells activities. (A) Inflammatory cytokines mRNA and (B) CB1 and CB2 mRNA in human hepatocytes by 2.5 µM AEA and 20 µM 2-AG; (C) Fibrosis-related mRNA in hHSC and hHSC co-cultivated with PBMC from CHC patients by 2.5 µM AEA and 20 µM 2-AG. * p < 0.05 vs corresponding non-treated control. Full article ">

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Open AccessArticle

Hepatitis A Virus Genotype Distribution during a Decade of Universal Vaccination of Preadolescents

by Lucía D’Andrea, Francisco J. Pérez-Rodríguez, Montserrat De Castellarnau, Sandra Manzanares, Josep Lite, Susana Guix, Albert Bosch and Rosa M. Pintó

Int. J. Mol. Sci. 2015, 16(4), 6842-6854; https://doi.org/10.3390/ijms16046842 - 25 Mar 2015

Cited by 18 | Viewed by 6377

Abstract

A universal vaccination program among preadolescents was implemented in Catalonia, Spain, during the period of 1999–2013 and its effectiveness has been clearly demonstrated by an overall significant attack rate reduction. However, reductions were not constant over time, and increases were again observed in [...] Read more.

A universal vaccination program among preadolescents was implemented in Catalonia, Spain, during the period of 1999–2013 and its effectiveness has been clearly demonstrated by an overall significant attack rate reduction. However, reductions were not constant over time, and increases were again observed in 2002–2009 due to the occurrence of huge outbreaks. In the following years, in the absence of large outbreaks, the attack rate decreased again to very low levels. However, an increase of symptomatic cases in the <5 age group has recently been observed. This is an unexpected observation since children younger than 6 are mostly asymptomatic. Such a long vaccination campaign offers the opportunity to analyze not only the effectiveness of vaccination, but also the influence of the circulating genotypes on the incidence of hepatitis A among the different age groups. This study has revealed the emergence of genotype IC during a foodborne outbreak, the short-lived circulation of vaccine-escape variants isolated during an outbreak among the men-having-sex-with-men group, and the association of genotype IIIA with the increase of symptomatic cases among the very young. From a public health perspective, two conclusions may be drawn: vaccination is better at an early age, and the vaccination schedule must be complete and include all recommended vaccine doses. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Figure 1
Hepatitis A attack rates in the decade 2004–2013 in Catalonia, Spain, in the context of a universal vaccination campaign for preadolescents at the age of 12 years. Data is distributed in natural years. Attack rates are defined as the number of cases per 100,000 inhabitants. Full article ">Figure 2
Hepatitis A attack rates for different age groups during the 2009–2013 period in Catalonia, Spain, in the context of a universal vaccination campaign for preadolescents at the age of 12 years. Data is distributed in natural years. Attack rates are defined as the number of cases per 100,000 inhabitants of each age group. Full article ">Figure 3
Hepatitis A attack rate of the 15–19 age group during the 2009–2013 period in Catalonia, Spain, in the context of a universal vaccination campaign for preadolescents at the age of 12 years. The 15–19 age group mostly includes young adults who have been vaccinated. Attack rates are defined as the number of cases per 100,000 inhabitants of the 15–19 age group. Full article ">Figure 4
Hepatitis A attack rates of different age groups during September 2011–August 2013 in Catalonia, Spain, in the context of a universal vaccination campaign of preadolescents at the age of 12 years. Data is distributed in two sets: September 2011–August 2012 and September 2012–August 2013. Attack rates are defined as the number of cases per 100,000 inhabitants of each age group. Full article ">Figure 5
Distribution of HAV genotypes in Catalonia, Spain, in the decade 2004–2013. A universal vaccination campaign of preadolescents at the age of 12 years started in 1999 and finished in 2013. Data is distributed in natural years. Genotypes are molecularly defined using the VP1X2A genomic region. Attack rates are defined as the number of cases per 100,000 inhabitants. Full article ">Figure 6
Phylogenetic trees based on the VP1/2A junction region, from strains belonging to subgenotype IA and IB. Neighbor-Joining, Kimura 2-parameter, bootstrap 1000 replicates. Full article ">Figure 7
Origin of the HAV strains isolated in the decade 2004–2013. Data is distributed in natural years. Attack rates are defined as the number of cases per 100,000 inhabitants. Full article ">

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Open AccessArticle

Favourable IFNL3 Genotypes Are Associated with Spontaneous Clearance and Are Differentially Distributed in Aboriginals in Canadian HIV-Hepatitis C Co-Infected Individuals

by Nasheed Moqueet, Claire Infante-Rivard, Robert W. Platt, Jim Young, Curtis Cooper, Mark Hull, Sharon Walmsley, Marina B. Klein and The Canadian Co-Infection Study Investigators

Int. J. Mol. Sci. 2015, 16(3), 6496-6512; https://doi.org/10.3390/ijms16036496 - 20 Mar 2015

Cited by 6 | Viewed by 6531

Abstract

Canadian Aboriginals are reported to clear Hepatitis C (HCV) more frequently. We tested the association of spontaneous clearance and three single nucleotide polymorphisms (SNPs) near the Interferon-lambda 3 (IFNL3) gene (rs12979860, rs8099917, functional variant rs8103142) and compared the SNP frequencies between HIV-HCV co-infected [...] Read more.

Canadian Aboriginals are reported to clear Hepatitis C (HCV) more frequently. We tested the association of spontaneous clearance and three single nucleotide polymorphisms (SNPs) near the Interferon-lambda 3 (IFNL3) gene (rs12979860, rs8099917, functional variant rs8103142) and compared the SNP frequencies between HIV-HCV co-infected whites and Aboriginals from the Canadian Co-infection Cohort. HCV treatment-naïve individuals with at least two HCV RNA tests were included (n = 538). A spontaneous clearance case was defined as someone with two consecutive HCV RNA-negative tests, at least six months apart. Data were analyzed using Cox proportional hazards adjusted for sex and ethnicity. Advantageous variants and haplotypes were more common in Aboriginals than Caucasians: 57% vs. 46% had the rs12979860 CC genotype, respectively; 58% vs. 48%, rs8103142 TT; 74% vs. 67%, the rs12979860 C allele; and 67% vs. 64% the TCT haplotype with three favourable alleles. The adjusted Hazard Ratios (95% CI) for spontaneous clearance were: rs12979860: 3.80 (2.20, 6.54); rs8099917: 5.14 (2.46, 10.72); and rs8103142: 4.36 (2.49, 7.62). Even after adjusting for rs12979860, Aboriginals and females cleared HCV more often, HR (95% CI) = 1.53 (0.89, 2.61) and 1.42 (0.79, 2.53), respectively. Our results suggest that favourable IFNL3 genotypes are more common among Aboriginals than Caucasians, and may partly explain the higher HCV clearance rates seen among Aboriginals. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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694 KiB

Open AccessArticle

Reactivation of Hepatitis B Virus in Hematopoietic Stem Cell Transplant Recipients in Japan: Efficacy of Nucleos(t)ide Analogues for Prevention and Treatment

by Shingo Nakamoto, Tatsuo Kanda, Chiaki Nakaseko, Emiko Sakaida, Chikako Ohwada, Masahiro Takeuchi, Yusuke Takeda, Naoya Mimura, Tohru Iseki, Shuang Wu, Makoto Arai, Fumio Imazeki, Kengo Saito, Hiroshi Shirasawa and Osamu Yokosuka

Int. J. Mol. Sci. 2014, 15(11), 21455-21467; https://doi.org/10.3390/ijms151121455 - 21 Nov 2014

Cited by 36 | Viewed by 7421

Abstract

We retrospectively reviewed 413 recipients with hematologic malignancies who underwent hematopoietic stem cell transplantation (HSCT) between June 1986 and March 2013. Recipients with antibody to hepatitis B core antigen (anti-HBc) and/or to hepatitis B surface antigen (anti-HBs) were regarded as experiencing previous hepatitis [...] Read more.

We retrospectively reviewed 413 recipients with hematologic malignancies who underwent hematopoietic stem cell transplantation (HSCT) between June 1986 and March 2013. Recipients with antibody to hepatitis B core antigen (anti-HBc) and/or to hepatitis B surface antigen (anti-HBs) were regarded as experiencing previous hepatitis B virus (HBV) infection. Clinical data of these recipients were reviewed from medical records. We defined ≥1 log IU/mL increase in serum HBV DNA from nadir as HBV reactivation in hepatitis B surface antigen (HBsAg)-positive recipients, and also defined ≥1 log IU/mL increase or re-appearance of HBV DNA and/or HBsAg as HBV reactivation in HBsAg-negative recipients. In 5 HBsAg-positive recipients, 2 recipients initially not administered with nucleos(t)ide analogues (NUCs) experienced HBV reactivation, but finally all 5 were successfully controlled with NUCs. HBV reactivation was observed in 11 (2.7%) of 408 HBsAg-negative recipients; 8 of these were treated with NUCs, and fortunately none developed acute liver failure. In 5 (6.0%) of 83 anti-HBc and/or anti-HBs-positive recipients, HBV reactivation occurred. None of 157 (0%) recipients without HBsAg, anti-HBs or anti-HBc experienced HBV reactivation. In HSCT recipients, HBV reactivation is a common event in HBsAg-positive recipients, or in HBsAg-negative recipients with anti-HBc and/or anti-HBs. Further attention should be paid to HSCT recipients with previous exposure to HBV. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Chronic Hepatitis B with Spontaneous Severe Acute Exacerbation

by Wei-Lun Tsai, Wei-Chi Sun and Jin-Shiung Cheng

Int. J. Mol. Sci. 2015, 16(12), 28126-28145; https://doi.org/10.3390/ijms161226087 - 26 Nov 2015

Cited by 19 | Viewed by 6895

Abstract

Chronic hepatitis B virus (HBV) infection is a major global health problem with an estimated 400 million HBV carriers worldwide. In the natural history of chronic hepatitis B (CHB), spontaneous acute exacerbation (AE) is not uncommon, with a cumulative incidence of 10%–30% every [...] Read more.

Chronic hepatitis B virus (HBV) infection is a major global health problem with an estimated 400 million HBV carriers worldwide. In the natural history of chronic hepatitis B (CHB), spontaneous acute exacerbation (AE) is not uncommon, with a cumulative incidence of 10%–30% every year. While exacerbations can be mild, some patients may develop hepatic decompensation and even die. The underlying pathogenesis is possibly related to the activation of cytotoxic T lymphocyte-mediated immune response against HBV. An upsurge of serum HBV DNA usually precedes the rise of alanine aminotransferase (ALT) and bilirubin. Whether antiviral treatment can benefit CHB with severe AE remains controversial, but early nucleos(t)ide analogues treatment seemed to be associated with an improved outcome. There has been no randomized study that compared the effects of different nucleos(t)ide analogues (NA) in the setting of CHB with severe AE. However, potent NAs with good resistance profiles are recommended. In this review, we summarized current knowledge regarding the natural history, pathogenetic mechanisms, and therapeutic options of CHB with severe AE. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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The clinical course of chronic hepatitis B (CHB) with acute exacerbation (AE) can be divided into four stages according to HBV DNA level. In the ascending limb, HBV DNA level <105 copies/mL denotes Stage I while HBV DNA level ≥105 copies/mL represents Stage II. In the descending limb, HBV DNA level ≥105 copies/mL denotes Stage III while HBV DNA level <105 copies/mL represents Stage IV. Full article ">Figure 2
Spontaneous AE of CHB is usually precipitated by reactivated infection, and there is usually an upsurge of serum HBV DNA prior to the abrupt elevation of ALT or bilirubin level. Red line: HBV DNA; Black line: Alanine Aminotransferase (ALT); Green line: Bilirubin. Full article ">Figure 3
Acute exacerbation of CHB is the result of dynamic changes of both innate and adaptive immune responses. Spontaneous AE of CHB is usually precipitated by reactivated infection, and there is usually an upsurge of serum HBV DNA prior to the abrupt elevation of alanine aminotransferase (ALT) or bilirubin level. Liver injury during these spontaneous AE appears to be mediated by T cells sensitized by HBV antigen presenting cells. Virus-specific CD8+ cytotoxic T cells (with help from CD4+ T cells) can recognize viral antigens presented on infected hepatocytes and lead to direct lysis of the infected hepatocyte. Non-parenchymal cells (NPC), dendritic cells, and macrophages can also produce interferon (IFN) α/β, cytokine and chemokine after recognition of HBV. Increased production of Th1 cytokines, Th2 cytokines, natural killer (NK) cell-mediated pathways, high serum levels of IFN-γ inducible chemokines Chemokine (C-X-C motif) ligand 9 (CXCL)-9 and CXCL-10, programmed cell death protein 1 (PD-1), and its ligand PD-L1, and activation of toll-like receptors (TLR) during AE of CHB are also observed in CHB with AE. IL: interleukin; NKT cell: natural killer T cell; Th1 cell: type I helper T cell; Th2 cell: type II helper T cell. Full article ">

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Epidemiology of Hepatitis E Virus in European Countries

by Daniele Lapa, Maria Rosaria Capobianchi and Anna Rosa Garbuglia

Int. J. Mol. Sci. 2015, 16(10), 25711-25743; https://doi.org/10.3390/ijms161025711 - 27 Oct 2015

Cited by 97 | Viewed by 9062

Abstract

Over the last decade the seroprevalence of immunoglobulin (IgG) anti hepatitis E virus (HEV) has been increasing in European countries and shows significant variability among different geographical areas. In this review, we describe the serological data concerning the general population and risk groups [...] Read more.

Over the last decade the seroprevalence of immunoglobulin (IgG) anti hepatitis E virus (HEV) has been increasing in European countries and shows significant variability among different geographical areas. In this review, we describe the serological data concerning the general population and risk groups in different European countries. Anti-HEV antibody prevalence ranged from 1.3% (blood donors in Italy) to 52% (blood donors in France). Various studies performed on risk groups in Denmark, Moldova and Sweden revealed that swine farmers have a high seroprevalence of HEV IgG (range 13%–51.1%), confirming that pigs represent an important risk factor in HEV infection in humans. Subtypes 3e,f are the main genotypes detected in the European population. Sporadic cases of autochthonous genotype 4 have been described in Spain, France, and Italy. Although most HEV infections are subclinical, in immune-suppressed and transplant patients they could provoke chronic infection. Fulminant hepatitis has rarely been observed and it was related to genotype 3. Interferon and ribavirin treatment was seen to represent the most promising therapy. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Interferon Response in Hepatitis C Virus (HCV) Infection: Lessons from Cell Culture Systems of HCV Infection

by Pil Soo Sung, Eui-Cheol Shin and Seung Kew Yoon

Int. J. Mol. Sci. 2015, 16(10), 23683-23694; https://doi.org/10.3390/ijms161023683 - 7 Oct 2015

Cited by 7 | Viewed by 5803

Abstract

Hepatitis C virus (HCV) is a positive-stranded RNA virus that infects approximately 130–170 million people worldwide. In 2005, the first HCV infection system in cell culture was established using clone JFH-1, which was isolated from a Japanese patient with fulminant HCV infection. JFH-1 [...] Read more.

Hepatitis C virus (HCV) is a positive-stranded RNA virus that infects approximately 130–170 million people worldwide. In 2005, the first HCV infection system in cell culture was established using clone JFH-1, which was isolated from a Japanese patient with fulminant HCV infection. JFH-1 replicates efficiently in hepatoma cells and infectious virion particles are released into the culture supernatant. The development of cell culture-derived HCV (HCVcc) systems has allowed us to understand how hosts respond to HCV infection and how HCV evades host responses. Although the mechanisms underlying the different outcomes of HCV infection are not fully understood, innate immune responses seem to have a critical impact on the outcome of HCV infection, as demonstrated by the prognostic value of IFN-λ gene polymorphisms among patients with chronic HCV infection. Herein, we review recent research on interferon response in HCV infection, particularly studies using HCVcc infection systems. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Hepatocellular Carcinoma in Patients with a Sustained Response to Anti-Hepatitis C Therapy

by Roberta D'Ambrosio, Cristina Della Corte and Massimo Colombo

Int. J. Mol. Sci. 2015, 16(8), 19698-19712; https://doi.org/10.3390/ijms160819698 - 19 Aug 2015

Cited by 54 | Viewed by 6265

Abstract

Hepatocellular carcinoma (HCC) is a common, life-threatening complication of longstanding infection with the hepatitis C virus (HCV), likely a consequence of the direct oncogenic activity of the virus cooperating with liver cell inflammation in transforming the liver into a mitogenic and mutagenic environment. [...] Read more.

Hepatocellular carcinoma (HCC) is a common, life-threatening complication of longstanding infection with the hepatitis C virus (HCV), likely a consequence of the direct oncogenic activity of the virus cooperating with liver cell inflammation in transforming the liver into a mitogenic and mutagenic environment. The achievement of a sustained virological response (SVR) to interferon-based therapies has been shown to benefit the course of hepatitis C in terms of reduced rates of liver-related complications and mortality from all causes. Interestingly, while achievement of an SVR is associated with a negligible risk of developing clinical decompensation over the years, the risk of HCC is not fully abrogated following HCV clearance, but it remains the dominant complication in all SVR populations. The factors accounting for such a residual risk of HCC in SVR patients are not fully understood, yet the persistence of the subverted architecture of the liver, diabetes and alcohol abuse are likely culprits. In the end, the risk of developing an HCC in SVR patients is attenuated by 75% compared to non-responders or untreated patients, whereas responders who develop an HCC may be stratified in different categories of HCC risk by a score based on the same demographic and liver disease-based variables, such as those that predict liver cancer in viremic patients. All in all, this prevents full understanding of those factors that drive HCC risk once HCV has been eradicated. Here, we critically review current understanding of HCC in SVR patients focusing on factors that predict residual risk of HCC among these patients and providing a glimpse of the expected benefits of new anti-HCV regimens based on direct antiviral agents. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Therapeutic Strategies and New Intervention Points in Chronic Hepatitis Delta Virus Infection

by Zhimin Guo and Thomas King

Int. J. Mol. Sci. 2015, 16(8), 19537-19552; https://doi.org/10.3390/ijms160819537 - 18 Aug 2015

Cited by 6 | Viewed by 7752

Abstract

Chronic hepatitis delta virus infection (CHD) is a condition arising from super-infection of hepatitis B virus (HBV)-infected patients, resulting in a more rapid advance in liver pathology and hepatocellular carcinoma than is observed for HBV mono-infection. Although hepatitis delta virus (HDV) is structurally [...] Read more.

Chronic hepatitis delta virus infection (CHD) is a condition arising from super-infection of hepatitis B virus (HBV)-infected patients, resulting in a more rapid advance in liver pathology and hepatocellular carcinoma than is observed for HBV mono-infection. Although hepatitis delta virus (HDV) is structurally simple, its life cycle involves the complex participation of host enzymes, HBV-derived surface antigen (HBsAg), and HDV-auto-ribozyme and hepatitis delta antigen (HDAg) activities. Unsatisfactory clinical trial results with interferon-based therapies are motivating researchers to adjust and redirect the approach to CHD drug development. This new effort will likely require additional structural and functional studies of the viral and cellular/host components involved in the HDV replication cycle. This review highlights recent work aimed at new drug interventions for CHD, with interpretation of key pre-clinical- and clinical trial outcomes and a discussion of promising new technological approaches to antiviral drug design. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Hepatitis C in Special Patient Cohorts: New Opportunities in Decompensated Liver Cirrhosis, End-Stage Renal Disease and Transplant Medicine

by Anna Hüsing, Iyad Kabar, Hartmut H. Schmidt and Hauke S. Heinzow

Int. J. Mol. Sci. 2015, 16(8), 18033-18053; https://doi.org/10.3390/ijms160818033 - 5 Aug 2015

Cited by 10 | Viewed by 8859

Abstract

Worldwide, hepatitis C virus (HCV) is a common infection. Due to new antiviral approaches and the approval of direct-acting antiviral agents (DAA), HCV therapy has become more comfortable. Nevertheless, there are special patient groups, in whom treatment of HCV is still challenging. Due [...] Read more.

Worldwide, hepatitis C virus (HCV) is a common infection. Due to new antiviral approaches and the approval of direct-acting antiviral agents (DAA), HCV therapy has become more comfortable. Nevertheless, there are special patient groups, in whom treatment of HCV is still challenging. Due to only few data available, tolerability and efficacy of DAAs in special patient cohorts still remain unclear. Such special patient cohorts comprise HCV in patients with decompensated liver disease (Child-Pugh Class B or C), patients with chronic kidney disease, and patients on waiting lists to renal/liver transplantation or those with HCV recurrence after liver transplantation. HCV infection in these patient cohorts has been shown to be associated with increased morbidity and mortality and may lead to reduced graft survival after transplantation. Successful eradication of HCV results in a better outcome concerning liver-related complications and in a better clinical outcome of these patients. In this review, we analyze available data and results from recently published literature and provide an overview of current recommendations of HCV-therapy regimen in these special patient cohorts. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Hepatitis B Virus Infection, MicroRNAs and Liver Disease

by Neelakshi Sarkar and Runu Chakravarty

Int. J. Mol. Sci. 2015, 16(8), 17746-17762; https://doi.org/10.3390/ijms160817746 - 3 Aug 2015

Cited by 42 | Viewed by 7910

Abstract

Hepatitis B virus (HBV) attacks the liver and can cause both acute as well as chronic liver diseases which might lead to liver cirrhosis and hepatocellular carcinoma. Regardless of the availability of a vaccine and numerous treatment options, HBV is a major cause [...] Read more.

Hepatitis B virus (HBV) attacks the liver and can cause both acute as well as chronic liver diseases which might lead to liver cirrhosis and hepatocellular carcinoma. Regardless of the availability of a vaccine and numerous treatment options, HBV is a major cause of morbidity and mortality across the world. Recently,microRNAs (miRNAs) have emerged as important modulators of gene function. Studies on the role of miRNA in the regulation of hepatitis B virus gene expression have been the focus of modern antiviral research. miRNAs can regulate viral replication and pathogenesis in a number of different ways, which includefacilitation, direct or indirect inhibition, activation of immune response, epigenetic modulation, etc. Nevertheless, these mechanisms can appropriately be used with a diagnosticand/or therapeutic approach. The present review is an attempt to classify specific miRNAs that are reported to be associated with various aspects of hepatitis B biology, in order to precisely present the participation of individual miRNAs in multiple aspects relating to HBV. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Progress and Prospects of Anti-HBV Gene Therapy Development

by Mohube B. Maepa, Ilke Roelofse, Abdullah Ely and Patrick Arbuthnot

Int. J. Mol. Sci. 2015, 16(8), 17589-17610; https://doi.org/10.3390/ijms160817589 - 31 Jul 2015

Cited by 35 | Viewed by 11502

Abstract

Despite the availability of an effective vaccine against hepatitis B virus (HBV), chronic infection with the virus remains a major global health concern. Current drugs against HBV infection are limited by emergence of resistance and rarely achieve complete viral clearance. This has prompted [...] Read more.

Despite the availability of an effective vaccine against hepatitis B virus (HBV), chronic infection with the virus remains a major global health concern. Current drugs against HBV infection are limited by emergence of resistance and rarely achieve complete viral clearance. This has prompted vigorous research on developing better drugs against chronic HBV infection. Advances in understanding the life cycle of HBV and improvements in gene-disabling technologies have been impressive. This has led to development of better HBV infection models and discovery of new drug candidates. Ideally, a regimen against chronic HBV infection should completely eliminate all viral replicative intermediates, especially covalently closed circular DNA (cccDNA). For the past few decades, nucleic acid-based therapy has emerged as an attractive alternative that may result in complete clearance of HBV in infected patients. Several genetic anti-HBV strategies have been developed. The most studied approaches include the use of antisense oligonucleotides, ribozymes, RNA interference effectors and gene editing tools. This review will summarize recent developments and progress made in the use of gene therapy against HBV. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Full article ">Figure 1
Diagram of hepatitis B virus (HBV) replication cycle. Attachment to the sodium taurocholate co-transporting polypeptide (NTCP) receptor, and possibly other receptors too, is the initiating event of infection (1); After uncoating and nuclear translocation of the capsid, relaxed circular DNA (rcDNA) is delivered to the nucleus (2); rcDNA is then repaired to form covalently closed circular DNA (cccDNA) (3); which is the template for transcription of viral RNA (4); Viral mRNA is translated (5); The pre-genomic RNA (pgRNA) is then packaged into capsid particles together with the viral Pol (6); The pgRNA is reverse transcribed in the nucleocapsid (7); And the viral particles are secreted via the endoplasmic reticulum (8). Sites of action of licensed and potentially therapeutic agents are indicated in red text. Viral cccDNA may be disabled by methods that employ gene editing. Exogenous activators of the RNA interference (RNAi) pathway may be employed to inactivate viral RNA. Nucleoside and nucleotide analogues, which are currently licensed drugs, may be used to inhibit reverse transcription of pgRNA. Full article ">Figure 2
Gene therapy strategies targeting HBV RNA. (A) Expressed or synthetic activators are incorporated into the RNA-Induced Silencing Complex (RISC) to redirect the RNAi pathway to silence viral target sequences; (B) Antisense oligonucleotides (ASOs) suppress gene expression by binding to target RNA through classical Watson–Crick base pairing to block translation or induce RNase H-mediated RNA cleavage; (C) Ribozymes do not rely on the host machinery for cleavage, but possess an enzymatic domain (Helix II in hammerhead ribozymes) that cleaves the target RNA following sequence specific binding of the RNA binding domains (Helix I and Helix III). These strategies result in HBV RNA degradation or suppression of viral protein translation. Full article ">Figure 3
Engineered nucleases used in genome and epigenome editing. (A) Zinc finger nucleases (ZFNs) containing three zinc finger modules recognize a nine-nucleotide target DNA sequence on the sense and antisense strands. FokI dimerization effects cleavage of both strands at the target site situated in the 5–7 nucleotide spacer region or cleavage domain; (B) Transcription activator-like effector nucleases (TALENs) comprise approximately 16 modules for each of the left and right subunits. Each module contains 33–35 amino acids that bind a single nucleotide at the repeat variable diresidue (RVD) at amino acids 12 and 13. Much like ZFNs, the FokI nuclease domain must dimerize to cleave each of the strands of the duplex DNA; (C) Clustered regulatory interspaced short palindromic repeats (CRISPR) and CRISPR associated (Cas) proteins system with single guide RNA (sgRNA) comprising a combination of naturally occurring CRISPR RNA (crRNA) and transactivating CRISPR RNA (tracrRNA). The sgRNA guides the Cas9 endonuclease by binding genomic DNA with the aid of an obligate upstream protospacer adjacent motif (PAM) sequence to effect site-specific cleavage. nt: nucleotide. Red asterisks: cleavage site. Full article ">

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Molecular Mechanisms to Control Post-Transplantation Hepatitis B Recurrence

by Akinobu Takaki, Tetsuya Yasunaka and Takahito Yagi

Int. J. Mol. Sci. 2015, 16(8), 17494-17513; https://doi.org/10.3390/ijms160817494 - 30 Jul 2015

Cited by 8 | Viewed by 6836

Abstract

Hepatitis B often progresses to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). Although newer nucleos(t)ide analogues result in >90% viral and hepatitis activity control, severely decompensated patients still need OLT because of drug-resistant virus, acute exacerbation, or hepatocellular carcinoma. Acute hepatitis B [...] Read more.

Hepatitis B often progresses to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). Although newer nucleos(t)ide analogues result in >90% viral and hepatitis activity control, severely decompensated patients still need OLT because of drug-resistant virus, acute exacerbation, or hepatocellular carcinoma. Acute hepatitis B is also an indication for OLT, because it can progress to fatal acute liver failure. After OLT, the hepatitis B recurrence rate is >80% without prevention, while >90% of transplant recipients are clinically controlled with combined hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogue treatment. However, long-term HBIG administration is associated with several unresolved issues, including limited availability and extremely high cost; therefore, several treatment protocols with low-dose HBIG, combined with nucleos(t)ide analogues, have been investigated. Another approach is to induce self-producing anti-hepatitis B virus (HBV) antibodies using an HBV envelope (HBs) antigen vaccine. Patients who are not HBV carriers, such as those with acutely infected liver failure, are good candidates for vaccination. For chronic HBV carrier liver cirrhosis patients, a successful vaccine response can only be achieved in selected patients, such as those treated with experimentally reduced immunosuppression protocols. The present protocol for post-OLT HBV control and the future prospects of newer treatment strategies are reviewed. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Hepatoma-Derived Growth Factor: Its Possible Involvement in the Progression of Hepatocellular Carcinoma

by Hirayuki Enomoto, Hideji Nakamura, Weidong Liu and Shuhei Nishiguchi

Int. J. Mol. Sci. 2015, 16(6), 14086-14097; https://doi.org/10.3390/ijms160614086 - 19 Jun 2015

Cited by 38 | Viewed by 7523

Abstract

The development of hepatocellular carcinoma (HCC) is an important complication of viral infection induced by hepatitis virus C, and our major research theme is to identify a new growth factor related to the progression of HCC. HDGF (hepatoma-derived growth factor) is a novel [...] Read more.

The development of hepatocellular carcinoma (HCC) is an important complication of viral infection induced by hepatitis virus C, and our major research theme is to identify a new growth factor related to the progression of HCC. HDGF (hepatoma-derived growth factor) is a novel growth factor that belongs to a new gene family. HDGF was initially purified from the conditioned medium of a hepatoma cell line. HDGF promotes cellular proliferation as a DNA binding nuclear factor and a secreted protein acting via a receptor-mediated pathway. HDGF is a unique multi-functional protein that can function as a growth factor, angiogenic factor and anti-apoptotic factor and it participates in the development and progression of various malignant diseases. The expression level of HDGF may be an independent prognostic factor for predicting the disease-free and overall survival in patients with various malignancies, including HCC. Furthermore, the overexpression of HDGF promotes the proliferation of HCC cells, while a reduction in the HDGF expression inhibits the proliferation of HCC cells. This article provides an overview of the characteristics of HDGF and describes the potential role of HDGF as a growth-promoting factor for HCC. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Structure of hepatoma-derived growth factor (HDGF). HDGF protein contains 240 amino acids. The N-terminal region of HDGF protein is highly homologous to that of HDGF-related proteins, and the well-conserved N-terminal amino acid sequence (approximately 100 amino acids) is represented as the HATH (homologous to the amino terminus of HDGF) domain. HDGF has two putative nuclear localization signals (NLSs). The first NLS is a basic amino acid-rich region (75 KPNKRK 80; basic residues underlined) in the HATH domain (NLS1), and HDGF protein also contains a basic motif (155 KRRAGLLEDSPKRPK 170; basic residues underlined) in the gene-specific region (NLS2). Full article ">Figure 2
Possible signal pathways of hepatoma-derived growth factor (HDGF). HDGF is a unique growth factor with dual mechanisms for promoting cellular proliferation: a receptor-mediated pathway and a direct action mediated by DNA binding following nuclear translocation. HDGF is considered to be secreted via a pathway that differs from the classical Golgi secretion system. Extracellular HDGF binds to an unidentified receptor and activates MAPK and/or PI3K. HDGF protein also acts as a nuclear protein that regulates the expression of target genes through DNA binding. Full article ">Figure 3
Roles of hepatoma-derived growth factor (HDGF) in the development and progression of malignant diseases. HDGF is a unique multi-functional protein that can function as a growth factor, angiogenic factor and anti-apoptotic factor and it participates in the development and progression of malignant diseases, including HCC. Full article ">

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Association of preS/S Mutations with Occult Hepatitis B Virus (HBV) Infection in South Korea: Transmission Potential of Distinct Occult HBV Variants

by Hong Kim and Bum-Joon Kim

Int. J. Mol. Sci. 2015, 16(6), 13595-13609; https://doi.org/10.3390/ijms160613595 - 15 Jun 2015

Cited by 27 | Viewed by 7733

Abstract

Occult hepatitis B virus infection (HBV) is characterized by HBV DNA positivity but HBV surface antigen (HBsAg) negativity. Occult HBV infection is associated with a risk of HBV transmission through blood transfusion, hemodialysis, and liver transplantation. Furthermore, occult HBV infection contributes to the [...] Read more.

Occult hepatitis B virus infection (HBV) is characterized by HBV DNA positivity but HBV surface antigen (HBsAg) negativity. Occult HBV infection is associated with a risk of HBV transmission through blood transfusion, hemodialysis, and liver transplantation. Furthermore, occult HBV infection contributes to the development of cirrhosis and hepatocellular carcinoma. We recently reported the characteristic molecular features of mutations in the preS/S regions among Korean individuals with occult infections caused by HBV genotype C2; the variants of preS and S related to severe liver diseases among chronically infected patients were also responsible for the majority of HBV occult infections. We also reported that HBsAg variants from occult-infected Korean individuals exhibit lower HBsAg secretion capacity but not reduced HBV DNA levels. In addition, these variants exhibit increased ROS-inducing capacity compared with the wild-type strain, linking HBV occult infections to liver cell damage. Taken together, our previous reports suggest the transmission potential of distinct HBV occult infection-related variants in South Korea. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Faldaprevir for the Treatment of Hepatitis C

by Tatsuo Kanda, Osamu Yokosuka and Masao Omata

Int. J. Mol. Sci. 2015, 16(3), 4985-4996; https://doi.org/10.3390/ijms16034985 - 4 Mar 2015

Cited by 13 | Viewed by 6309

Abstract

The current treatments for chronic hepatitis C virus (HCV) genotype 1 infection are combinations of direct-acting antivirals, and faldaprevir is one of the new generation of HCV NS3/4A protease inhibitors. At the end of 2013, the US Food and Drug Administration (FDA) approved [...] Read more.

The current treatments for chronic hepatitis C virus (HCV) genotype 1 infection are combinations of direct-acting antivirals, and faldaprevir is one of the new generation of HCV NS3/4A protease inhibitors. At the end of 2013, the US Food and Drug Administration (FDA) approved the HCV NS3/4A protease inhibitor simeprevir and the HCV NS5B polymerase inhibitor sofosbuvir. Simeprevir or sofosbuvir in combination with pegylated interferon and ribavirin are available for clinical use. Faldaprevir, another HCV NS3/4A protease inhibitor that also has fewer adverse events than telaprevir or boceprevir, is under development. Of interest, faldaprevir in combination with pegylated interferon and ribavirin, and interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin provides high sustained virological response rates for HCV genotype 1 infection. The aim of this article is to review these data concerning faldaprevir. Faldaprevir in combination with pegylated interferon and ribavirin treatment appears to be associated with fewer adverse events than telaprevir or boceprevir in combination with pegylated interferon and ribavirin, and may be one of the therapeutic options for treatment-naive patients with HCV genotype 1. The interferon-free combination of faldaprevir and deleobuvir with ribavirin was effective for HCV genotype 1 infection and may hold promise for interferon-ineligible and interferon-intolerant patients. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Chemical structure of faldaprevir. Full article ">Figure 2
Safety, and antIviraL Effect of faldaprevir iN hepatitis C (SILEN) trial designs and results. (A) The SILEN-C1 trial consisted of faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naive patients with chronic genotype-1 hepatitis C virus (HCV) [<a href="#B25-ijms-16-04985" class="html-bibr">25</a>]. A total of 429 treatment-naive patients without cirrhosis were randomized 1:1:2:2 to receive 24 weeks of pegylated interferon alfa-2a and ribavirin (PR) in combination with placebo (N = 71), faldaprevir 120 mg once daily (QD) with 3 days of PR lead-in (LI*) (N = 69), 240 mg QD with LI (N = 143), or 240 mg QD without LI (N = 146), followed by an additional 24 weeks of PR. The rates of sustained virological response 24 weeks after therapy (SVR24) are indicated. mRVR, maintained rapid virological response defined as HCV viral load (VL) below the lower limit of quantification (LLOQ) at week 4 (HCV RNA < 25 IU/mL) and undetectable from week 8 to week 20 (HCV RNA < 17 IU/mL). Randomization 1:1 of patients with mRVR to 24 weeks versus 48 weeks of PR; (B) The SILEN-C2 trial consisted of faldaprevir combined with pegylated interferon alfa-2a and ribavirin in chronic HCVgenotype 1-infected patients with prior nonresponse [<a href="#B26-ijms-16-04985" class="html-bibr">26</a>]. A total of 290 noncirrhotic patients with prior null (<1 log10 VL drop at any time during treatment) or partial response (≥1 log10 VL drop but never undetectable during treatment) were randomized 2:1:1 to receive 48 weeks of PR in combination with faldaprevir 240 mg QD with 3 days PR lead-in (LI) (N = 142), 240 mg QD without LI (N = 76), or 240 mg twice daily (BID) with LI (N = 70). Full article ">Figure 3
Results of a phase 2 study of faldaprevir (FDV) plus pegylated interferon (P) and ribavirin (R) in Japanese patients with chronic HCV genotype 1 infection [<a href="#B27-ijms-16-04985" class="html-bibr">27</a>]. Treatment-naive patients received FDV 120 or 240 mg QD, or placebo, plus PR for 4 weeks, then PR alone for 44 weeks. Treatment-experienced patients received FDV 240 mg QD plus PR for 4 weeks, then PR alone for 44 weeks. The rates of sustained virological response 24 weeks after therapy (SVR24) are shown. Full article ">Figure 4
Safety and antiviral effect of Oral combinations withoUt iNnterferon in patients Diagnosed with chronic hepatitis C (SOUND) trial designs and results. (A,B) The clinical phase 1b trial (SOUND-C1) consisted of faldaprevir in combination with deleobuvir and ribavirin for 4 weeks in treatment-naive patients with chronic genotype 1 HCV [<a href="#B28-ijms-16-04985" class="html-bibr">28</a>]. (A) In patients treated with deleobuvir 400 mg 3 times daily + faldaprevir 120 mg once daily + ribavirin, virological response (HCV RNA level less than 25 IU/mL) by the duration of treatment and genotype. White column, HCV subgenotype 1a; gray column, HCV subgenotype 1b; black column, HCV subgenotypes 1a and 1b; (B) In patients treated with deleobuvir 600 mg 3 times daily + faldaprevir 120 mg once daily + ribavirin, virological response (HCV RNA level less than 25 IU/mL) by the duration of treatment and genotype; (C) In the clinical phase 2b trial (SOUND-C2) [<a href="#B29-ijms-16-04985" class="html-bibr">29</a>], treatment regimens were as follows: faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, plus ribavirin (R), for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg twice daily*, plus ribavirin (R), for 28 weeks (BID28W); and faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, without ribavirin, for 28 weeks (TID28W-NR). The rates of sustained virological response 12 weeks after therapy (SVR12) are shown. Full article ">Figure 4 Cont.
Safety and antiviral effect of Oral combinations withoUt iNnterferon in patients Diagnosed with chronic hepatitis C (SOUND) trial designs and results. (A,B) The clinical phase 1b trial (SOUND-C1) consisted of faldaprevir in combination with deleobuvir and ribavirin for 4 weeks in treatment-naive patients with chronic genotype 1 HCV [<a href="#B28-ijms-16-04985" class="html-bibr">28</a>]. (A) In patients treated with deleobuvir 400 mg 3 times daily + faldaprevir 120 mg once daily + ribavirin, virological response (HCV RNA level less than 25 IU/mL) by the duration of treatment and genotype. White column, HCV subgenotype 1a; gray column, HCV subgenotype 1b; black column, HCV subgenotypes 1a and 1b; (B) In patients treated with deleobuvir 600 mg 3 times daily + faldaprevir 120 mg once daily + ribavirin, virological response (HCV RNA level less than 25 IU/mL) by the duration of treatment and genotype; (C) In the clinical phase 2b trial (SOUND-C2) [<a href="#B29-ijms-16-04985" class="html-bibr">29</a>], treatment regimens were as follows: faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, plus ribavirin (R), for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg twice daily*, plus ribavirin (R), for 28 weeks (BID28W); and faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, without ribavirin, for 28 weeks (TID28W-NR). The rates of sustained virological response 12 weeks after therapy (SVR12) are shown. Full article ">

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Open AccessReview

Significant Roles of Regulatory T Cells and Myeloid Derived Suppressor Cells in Hepatitis B Virus Persistent Infection and Hepatitis B Virus-Related HCCs

by Yasuteru Kondo and Tooru Shimosegawa

Int. J. Mol. Sci. 2015, 16(2), 3307-3322; https://doi.org/10.3390/ijms16023307 - 3 Feb 2015

Cited by 46 | Viewed by 6602

Abstract

The adaptive immune system, including type1 helper T cells (Th1 cells), cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs), plays an important role in the control of hepatitis B virus (HBV). On the other hand, regulatory T cells (Tregs) and myeloid derived suppressor [...] Read more.

The adaptive immune system, including type1 helper T cells (Th1 cells), cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs), plays an important role in the control of hepatitis B virus (HBV). On the other hand, regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) suppress the immune reaction in HBV and hepatocellular carcinoma (HCC). Excessive activation of immune suppressive cells could contribute to the persistent infection of HBV and the progression of HCC. The frequency and/or function of Tregs could affect the natural course in chronic hepatitis B patients and the treatment response. In addition to the suppressive function of MDSCs, MDSCs could affect the induction and function of Tregs. Therefore, we should understand in detail the mechanism by which Tregs and MDSCs are induced to control HBV persistent infection and HBV-related HCC. Immune suppressive cells, including Tregs and MDSCs, contribute to the difficulty in inducing an effective immune response for HBV persistent infection and HBV-related HCC. In this review, we focus on the Tregs and MDSCs that could be potential targets for immune therapy of chronic hepatitis B and HBV-related HCC. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Open AccessCase Report

Successful and Safe Long-Term Standard Antiviral Therapy in a Patient with “Explosive” Immune Response in Course of HCV-Related Liver Cirrhosis

by Paolo Conca, Giovanni Cafaro, Amalia De Renzo, Antonio Coppola, Ernesto Cimino and Giovanni Tarantino

Int. J. Mol. Sci. 2015, 16(6), 14075-14085; https://doi.org/10.3390/ijms160614075 - 19 Jun 2015

Cited by 5 | Viewed by 6531

Abstract

Hepatitis C virus (HCV) has been recognized to be both a hepato- and lymphotropic virus. HCV lymphotropism represents an essential detail in the pathogenesis of virus-related autoimmune and lymphoproliferative disorders, ranging from clonal expansion of B-cells with organ and non-organ-specific autoantibody production up [...] Read more.

Hepatitis C virus (HCV) has been recognized to be both a hepato- and lymphotropic virus. HCV lymphotropism represents an essential detail in the pathogenesis of virus-related autoimmune and lymphoproliferative disorders, ranging from clonal expansion of B-cells with organ and non-organ-specific autoantibody production up to overt non-Hodgkin’s lymphoma along a continuous step-by-step model of B-cell lymphomagenesis, where the intermediated mixed cryoglobulinemia could be considered as a stage of suppressible antigen-driven lymphoproliferation. The HCV long-lasting extrahepatic replicative state generates an abnormal systemic immunological response, including rheumatoid factor (RF) and cryo- and non-cryoprecipitable immune complexes, as well as clinical manifestations, comprising dermatitis, polyarthralgias and arthritis, pulmonary disease, aplastic anemia, glomerulonephritis and vasculitis. The mechanism of these extra-hepatic disorders is thought of as linked to immune complex disease, but their pathogenesis is poorly clarified. Immune-suppressive treatment could induce high-level hepatitis C viremia and impair hepatic disease. We report a female patient, whose chronic HCV-related liver cirrhosis with associated explosive, but oligosymptomatic lymphoproliferative immune response, i.e., RF beyond three thousand times the upper of normal range (unr), type II cryoglobulinemia with cryocrit 40% and monoclonal gammopathy IgM-k, has been successfully and safely treated by long-lasting (sixty-six months) combined antiviral therapy (pegylated interferon alfa and ribavirin), at moderate and tapering dose regimen, prolonged for nearly 24 months after the first viral suppression. At the last follow-up (fifty-one months), the patient was showing very-long term antiviral response, progressive decline of secondary immune activation and absence of significant side-effects. Further research is required to fully verify the real impact on therapeutic choice/regimen. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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