4New Hepatitis C Abstracts

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J Viral Hepat. 2011 Oct;18(10):e568-77. doi: 10.1111/j.1365-2893.2011.01487.x.

Epub 2011 Jul 1.

Association of filamin A and vimentin with hepatitis C virus proteins in

infected human hepatocytes.

Ghosh S, Ahrens WA, Phatak SU, Hwang S, Schrum LW, Bonkovsky HL.

Source

The Liver-Biliary-Pancreatic Center and the Liver, Digestive and Metabolic

Disorders Laboratory, Carolinas Medical Center, Charlotte, NC School of

Medicine, the University of North Carolina, Charlotte Campus, NC The University

of North Carolina at Charlotte, Charlotte, NC Department of Medicine, the

University of North Carolina at Chapel Hill, Chapel Hill, NC Departments of

Medicine and Molecular, Microbial & Structural Biology, the University of

Connecticut Health Center, Farmington, CT, USA.

Abstract

Summary.  Chronic hepatitis C (CHC) infection caused by hepatitis C virus

(HCV) is a major cause of liver disease and remains a major therapeutic

challenge. A variety of host proteins interact with HCV proteins. The definitive

role of cytoskeletal (CS) proteins in HCV infection remains to be determined. In

this study, our aim was to determine the expression profile of differentially

regulated and expressed selected CS proteins and their association with HCV

proteins in infected hepatocytes as possible therapeutic targets. Using

proteomics, qRT-PCR, Western blot and immunofluorescence techniques, we revealed

that filamin A (fila) and vimentin (vim) were prominently increased proteins in

HCV-expressing human hepatoma cells compared with parental cells and in liver

biopsies from patients with CHC vs controls. HCV nonstructural (NS) 3 and NS5A

proteins were associated with fila, while core protein partially with fila and

vim. Immunoprecipitation showed interactions among fila and NS3 and NS5A

proteins. Cells treated with interferon-α showed a dose- and time-dependent

decrease in CS and HCV proteins. NS proteins clustered at the perinuclear region

following cytochalasin b treatment, whereas disperse cytoplasmic and perinuclear

distribution was observed in the no-treatment group. This study demonstrates and

signifies that changes occur in the expression of CS proteins in HCV-infected

hepatocytes and, for the first time, shows the up-regulation and interaction of

fila with HCV proteins. Association between CS and HCV proteins may have

implications in future design of CS protein-targeted therapy for the treatment

for HCV infection.

© 2011 Blackwell Publishing Ltd.

PMID: 21914078 [PubMed - in process]

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J Viral Hepat. 2011 Oct;18(10):e561-7. doi: 10.1111/j.1365-2893.2011.01478.x.

Epub 2011 May 25.

Correlation between hyporesponsiveness to Toll-like receptor ligands and liver

dysfunction in patients with chronic hepatitis C virus infection.

Chung H, Watanabe T, Kudo M, Chiba T.

Source

Department of Gastroenterology and Hepatology, Kinki University School of

Medicine, Osaka-Sayama, Osaka, Japan Department of Gastroenterology and

Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan Center

for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University

Graduate School of Medicine, Kyoto, Japan.

Abstract

Summary.  Hepatitis C virus (HCV)-associated antigens, such as the core and

nonstructural antigens, activate host innate immune systems via Toll-like

receptors (TLRs). We previously showed that chronic exposure to the core antigen

induces hyporesponsiveness to TLR ligands in antigen-presenting cells via

activation of TLR2 and that stimulation with TLR ligands results in impaired

IL-6 production by peripheral blood monocytes from HCV-infected patients. In the

present study, peripheral blood mononuclear cells (PBMCs) isolated from patients

with chronic HCV or hepatitis B virus (HBV) infection were stimulated with TLR

ligands to determine the production of IL-6 and IL-8 and to identify the

clinical parameters associated with hyporesponsiveness to TLR ligands in

patients with chronic HCV infection. The results showed that pro-inflammatory

cytokine responses to TLR ligands were suppressed in PBMCs isolated from

HCV-infected, but not HBV-infected, patients. The reduced cytokine responses to

TLR ligands seen in HCV-infected patients correlated with platelet counts and

serum prothrombin time levels. In contrast, there was no correlation between

TLR-induced cytokine responses and serum levels of core antigen. Thus,

hyporesponsiveness to TLR ligands in HCV-infected patients is correlated with

liver dysfunction. In conclusion, both host factors and viral factors may be

involved in the generation of hyporesponsiveness to TLR ligands in patients with

chronic HCV infection.

© 2011 Blackwell Publishing Ltd.

PMID: 21914077 [PubMed - in process]

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J Viral Hepat. 2011 Oct;18(10):e550-60. doi: 10.1111/j.1365-2893.2011.01468.x.

Epub 2011 May 23.

IL28B polymorphism may guide pegylated interferon plus ribavirin therapy even

after curative treatment for hepatitis C virus-related hepatocellular carcinoma.

Kawaoka T, Aikata H, Takaki S, Hiramatsu A, Waki K, Hiraga N, Miki D, Tsuge M,

Imamura M, Kawakami Y, Takahashi S, Ochi H, Tashiro H, Ohdan H, ma K.

Source

Department of Medicine and Molecular Science, Division of Frontier Medical

Science, Minami-ku, Hiroshima University, Hiroshima, Japan Laboratory for

Digestive Diseases, Centre for Genomic Medicine, RIKEN (The Institute of

Physical and Chemical Research), Minami-ku, Hiroshima, Japan Department of

Surgery, Division of Frontier Medical Science, Programs for Biomedical Research,

Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan.

Abstract

Summary.  The present study was designed to determine the predictive factors

for the viral response to pegylated interferon-alpha plus ribavirin combination

therapy (PEGIFN/RBV) administered after curative treatment for hepatitis C virus

(HCV)-related hepatocellular carcinoma (HCC). The study group was 78 patients

treated between January 2005 and January 2009. The sustained viral response

(SVR) rate was 25.8% (15/58) in patients infected with HCV-genotype 1 and 55.0%

(11/20) in those with genotype 2. Among the 78 patients, 32 (41.0%) could not

complete the treatment protocol, and this was because of HCC recurrence in 17

(53%) of them. Multivariate analysis identified partial early viral response

(pEVR) as the only independent determinant of SVR [odds ratio (OR) 14.73,

P = 0.013] for patients with genotype 1. Multivariate analysis identified

male gender (OR 8.72, P = 0.001) and interleukin-28B (IL-28B) genotype

(rs8099917) TT (OR 7.93, P = 0.007) as independent predictors of pEVR.

Multivariate analysis also identified IL-28B genotype GG+TG (OR 14.1,

P = 0.021) and α-fetoprotein >30 (OR 5.4, P = 0.031) as independent

predictors of null response. Patients with SVR showed a better survival rate

than those without SVR (P = 0.034). The second HCC recurrence rate tended to

be lower in patients with SVR than in those without SVR (P = 0.054). With

regard to the prognosis of patients with SVR, it is desirable to achieve SVR

with interferon therapy even when administered after HCC treatment. IL-28B

genotype is a potentially useful marker for the response to PEGIFN/RBV therapy

administered after curative treatment of HCV-related HCC.

© 2011 Blackwell Publishing Ltd.

PMID: 21914076 [PubMed - in process]

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J Viral Hepat. 2011 Oct;18(10):e541-9. doi: 10.1111/j.1365-2893.2011.01464.x.

Cellular immune responses and occult infection in seronegative heterosexual

partners of chronic hepatitis C patients.

Roque-Cuéllar MC, Sánchez B, García-Lozano JR, Praena-Fernández JM,

Núñez-Roldán A, Aguilar-Reina J.

Source

Grupo Sección de Hepatología, Servicio de Aparato Digestivo Hospital

Universitario Virgen del Rocío de Sevilla Servicio de Inmunología, Hospital

Universitario Virgen del Rocío de Sevilla Unidad de Metodología y Evaluación

de la Investigación. Fundación Pública Andaluza para la Gestión de la

Investigación en Salud de Sevilla (FISEVI), IBIS. Hospital Universitario Virgen

del Rocío de Sevilla, Spain.

Abstract

Summary.  It is unknown whether hepatitis C virus (HCV)-specific cellular

immune responses can develop in seronegative sexual partners of chronically

HCV-infected patients and whether they have occult infection. Thirty-one

heterosexual partners of patients with chronic HCV were studied, fifteen of them

with HCV transmission risks. Ten healthy individuals and 17 anti-HCV

seropositive patients, without viremia, were used as controls. Virus-specific

CD4+ and CD8+ T-cell responses were measured by flow cytometry against six HCV

peptides, situated within the nonstructural (NS) proteins NS3, NS4 and NS5,

through intracellular detection of gamma interferon (IFN-γ) or interleukin 4

(IL-4) production and CD69 expression. Sexual partners had a higher production

of IFN-γ and IL-4 by CD4+ cells against NS3-p124 (P = 0.003), NS5b-p257

(P = 0.005) and NS5b-p294 (P = 0.012), and CD8+ cells against NS3-p124

(P = 0.002), NS4b-p177 (P = 0.001) and NS3-p294 (P = 0.004) as

compared with healthy controls. We observed elevated IFN-γ production by CD4+ T

cells against NS5b-p257 (P = 0.042) and NS5b-p294 (P = 0.009) in the

sexual partners with HCV transmission risks (sexual, professional and familial

altogether) than in those without risks. RNA was extracted from peripheral blood

mononuclear cells (PBMC), and detection of HCV-RNA positive and replicative

(negative) strands was performed by strand-specific real-time PCR. In four

sexual partners, the presence of positive and negative HCV- RNA strands in PBMC

was confirmed. Hence, we found an HCV-specific cellular immune response as well

as occult HCV infection in seronegative and aviremic sexual partners of

chronically HCV-infected patients.

© 2011 Blackwell Publishing Ltd.

PMID: 21914075 [PubMed - in process]

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