5 New HCV Abstracts

January 29, 2011

Hepatology. 2011 Jan;53(1):32-41. doi: 10.1002/hep.23985. Epub 2010 Oct 26.

Ribavirin potentiates interferon action by augmenting interferon-stimulated gene

induction in hepatitis C virus cell culture models.

E, Feld JJ, Li Q, Hu Z, Fried MW, Liang TJ.

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney

Diseases, National Institutes of Health, Bethesda, MD.

Abstract

The combination of pegylated interferon (PEG-IFN) and ribavirin is the standard

treatment for chronic hepatitis C. Our recent clinical study suggests that

ribavirin augments the induction of interferon-stimulated genes (ISGs) in

patients treated for hepatitis C virus (HCV) infection. In order to further

characterize the mechanisms of action of ribavirin, we examined the effect of

ribavirin treatment on ISG induction in cell culture. In addition, the effect of

ribavirin on infectious HCV cell culture systems was studied. Similar to

interferon (IFN)-Î±, ribavirin potently inhibits JFH-1 infection of Huh7.5.1

cells in a dose-dependent manner, which spans the physiological concentration of

ribavirin in vivo. Microarray analysis and subsequent quantitative polymerase

chain reaction assays demonstrated that ribavirin treatment resulted in the

induction of a distinct set of ISGs. These ISGs, including IFN regulatory

factors 7 and 9, are known to play an important role in anti-HCV responses. When

ribavirin is used in conjunction with IFN-Î±, induction of specific ISGs is

synergistic when compared with either drug applied separately. Direct

up-regulation of these antiviral genes by ribavirin is mediated by a novel

mechanism different from those associated with IFN signaling and intracellular

double-stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference

studies excluded the activation of the Toll-like receptor and nuclear factor ÎºB

pathways in the action of ribavirin. Conclusion: Our study suggests that

ribavirin, acting by way of a novel innate mechanism, potentiates the anti-HCV

effect of IFN. Understanding the mechanism of action of ribavirin would be

American Association for the Study of Liver Diseases.

PMID: 21254160 [PubMed - in process]

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22.

Hepatology. 2011 Jan;53(1):23-31. doi: 10.1002/hep.23980. Epub 2010 Dec 13.

Improved dendritic cell-based immunization against hepatitis C virus using

peptide inhibitors of interleukin 10.

DÃaz-ValdÃ©s N, Manterola L, BelsÃºe V, Riezu-Boj JI, Larrea E, Echeverria I,

LlÃ³piz D, LÃ³pez-Sagaseta J, Lerat H, Pawlotsky JM, Prieto J, Lasarte JJ,

BorrÃ¡s-Cuesta F, Sarobe P.

From the Division of Hepatology and Gene Therapy, Center for Applied Medical

Research (CIMA), University of Navarra, Pamplona, Spain.

Abstract

The high levels of interleukin 10 (IL-10) present in chronic hepatitis C virus

(HCV) infection have been suggested as responsible for the poor antiviral

cellular immune responses found in these patients. To overcome the

immunosuppressive effect of IL-10 on antigen-presenting cells such as dendritic

cells (DCs), we developed peptide inhibitors of IL-10 to restore DC functions

and concomitantly induce efficient antiviral immune responses. Two IL-10-binding

peptides (p9 and p13) were selected using a phage-displayed library and their

capacity to inhibit IL-10 was assessed in a bioassay and in STAT-3 (signal

transducer and activator of transcription 3) phosphorylation experiments in

vitro. In cultures of human leukocytes where HCV core protein induces the

production of IL-10, p13 restored the ability of plasmacytoid DC to produce

interferon alpha (IFN-Î±) after Toll-like receptor 9 (TLR9) stimulation.

Similarly, when myeloid DCs were stimulated with CD40L in the presence of HCV

core, p9 enhanced IL-12 production by inhibiting HCV core-induced as well as

CD40L-induced IL-10. Moreover, in vitro, p13 potentiated the effect of

maturation stimuli on human and murine DC, increasing their IL-12 production and

stimulatory activity, which resulted in enhanced proliferation and IFN-Î³

production by responding T-cells. Finally, immunization with p13-treated murine

DC induced stronger anti-HCV T-cell responses not only in wildtype mice but also

in HCV transgenic mice and in mice transiently expressing HCV core in the liver.

Conclusion: These results suggest that IL-10 inhibiting peptides may have

important applications to enhance anti-HCV immune responses by restoring the

American Association for the Study of Liver Diseases.

PMID: 21254159 [PubMed - in process]

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23.

Hepatology. 2011 Jan;53(1):14-22. doi: 10.1002/hep.24056.

Quantitation of pretreatment serum interferon-Î³-inducible protein-10 improves

the predictive value of an IL28B gene polymorphism for hepatitis C treatment

response.

Darling JM, Aerssens J, Fanning G, McHutchison JG, Goldstein DB, AJ,

Shianna KV, Afdhal NH, Hudson ML, Howell CD, Talloen W, Bollekens J, De Wit M,

Scholliers A, Fried MW.

University of North Carolina, Chapel Hill, NC.

Abstract

Polymorphisms of the IL28B gene are highly associated with sustained virological

response (SVR) in patients with chronic hepatitis C treated with peginterferon

and ribavirin. Quantitation of interferon-Î³-inducible protein-10 (IP-10) may

also differentiate antiviral response. We evaluated IP-10 levels in pretreatment

serum from 115 nonresponders and 157 sustained responders in the Study of Viral

Resistance to Antiviral Therapy of Chronic Hepatitis C cohort, including African

American (AA) and Caucasian American (CA) patients. Mean IP-10 was lower in

sustained responders compared with nonresponders (437 Â± 31 vs 704 Â± 44 pg/mL,

P < 0.001), both in AA and CA patients. The positive predictive value of low

IP-10 levels (<600 pg/mL) for SVR was 69%, whereas the negative predictive value

of high IP-10 levels (>600 pg/mL) was 67%. We assessed the combination of

pretreatment IP-10 levels with IL28B genotype as predictors of treatment

response. The IL28B polymorphism rs12979860 was tested in 210 participants. The

CC, CT, and TT genotypes were found in 30%, 49%, and 21% of patients,

respectively, with corresponding SVR rates of 87%, 50%, and 39% (P < 0.0001).

Serum IP-10 levels within the IL28B genotype groups provided additional

information regarding the likelihood of SVR (P < 0.0001). CT carriers with low

IP-10 had 64% SVR versus 24% with high IP-10. Similarly, a higher SVR rate was

identified for TT and CC carriers with low versus high IP-10 (TT, 48% versus

20%; CC, 89% versus 79%). IL28B genotype and baseline IP-10 levels were additive

but independent when predicting SVR in both AA and CA patients. Conclusion: When

IL28B genotype is combined with pretreatment serum IP-10 measurement, the

predictive value for discrimination between SVR and nonresponse is significantly

improved, especially in non-CC genotypes. This relationship warrants further

investigation to elucidate the mechanisms of antiviral response and prospective

Study of Liver Diseases.

PMID: 21254158 [PubMed - in process]

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24.

Hepatology. 2011 Jan;53(1):7-13. doi: 10.1002/hep.23976.

Role of interleukin-28B polymorphisms in the treatment of hepatitis C virus

genotype 2 infection in Asian patients.

Yu ML, Huang CF, Huang JF, Chang NC, Yang JF, Lin ZY, Chen SC, Hsieh MY, Wang

LY, Chang WY, Li YN, Wu MS, Dai CY, Juo SH, Chuang WL.

Internal Medicine , Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan;

Faculty of Internal Medicine, College of Medicine, Kaohsiung, Taiwan; Internal

Medicine.

Abstract

Genome-wide association studies have linked single nucleotide polymorphisms

(SNPs) near the interleukin-28B gene to the hepatitis C virus genotype 1 (HCV-1)

response to peginterferon/ribavirin treatment. We aimed to explore the impact on

the treatment outcomes of Asian HCV-2 patients. We determined rs8105790,

rs8099917, rs4803219, and rs10853728 to be candidate SNPs in 482 Asian HCV-2

patients treated with the standard of care. Because the first three SNPs were in

very strong linkage disequilibrium with one another (r2 = 0.94-0.96), rs8099917

and rs10853728 were selected for an analysis of their influence on the

achievement of rapid virological response [RVR; seronegativity for hepatitis C

virus (HCV) RNA in treatment week 4] and sustained virological response (SVR;

seronegativity for HCV RNA throughout 24 weeks of posttreatment follow-up). The

rs10853728 genotype did not predict RVR or SVR in HCV-2 patients. However,

patients with the rs8099917 TT genotype, in comparison with patients with GT/GG

genotypes, had a significantly higher rate of achieving RVR (85.2% versus 72.0%,

P = 0.017) but did have not a significantly higher rate of achieving SVR (89.4%

versus 86.0%). Multivariate analysis revealed that a baseline HCV viral load

<400,000 IU/mL was the strongest predictor of RVR [odds ratio (OR) = 4.27, 95%

confidence interval (CI) = 2.31-7.87, P < 0.001], and this was followed by

advanced liver fibrosis (OR = 0.28, 95% CI = 0.15-0.53, P < 0.001), the carriage

of the rs8099917 TT genotype (OR = 3.10, 95% CI = 1.34-7.21, P = 0.008), and the

pretreatment level of aspartate aminotransferase (OR = 0.996, 95% CI =

0.99-1.00, P = 0.04). Nevertheless, the achievement of RVR was the single

predictor of SVR with an OR of 19.37 (95% CI = 8.89-42.23, P < 0.001), whereas

the rs8099917 genotypes played no role in achieving SVR with or without RVR.

Conclusion: The rs8099917 TT genotype is significantly independently predictive

of RVR, which is the single best predictor of SVR, in Asian HCV-2 patients.

Diseases.

PMID: 21254157 [PubMed - in process]

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25.

J Hepatol. 2011 Jan 22. [Epub ahead of print]

Down-regulation of intra-hepatic T-cell signaling associated with GB virus C in

a HCV/HIV co-infected group with reduced liver disease.

Berzsenyi MD, Woollard DJ, McLean CA, Preiss S, Perreau VM, Beard MR, Bowden DS,

Cowie BC, Li S, Mijch AM, SK.

Department of Gastroenterology, Alfred Hospital, Commercial Road, Prahran 3181,

, Australia.

Abstract

BACKGROUND & AIMS: Studies have shown GB virus C (GBV-C) infection leads to

reduced liver disease in hepatitis C virus (HCV) /human immunodeficiency virus

(HIV) co-infection. Mechanism(s) responsible are unknown. We aim to identify

differential gene and protein expression associated with GBV-C in HCV/HIV

co-infection that may be responsible for reduced liver disease.

METHODS: Liver, PBMCs and plasma were collected from 43 HCV/HIV patients. Plasma

was tested for GBV-C RNA by RT-PCR with NS5B gene primers. Microarray was

performed on liver and RT-qPCR in liver/PBMCs. Hepatic protein expression was by

immunohistochemistry.

RESULTS: Sixteen of 43 patients had GBV-C RNA. GBV-C was associated with reduced

hepatic fibrosis (P=0.005) and inflammation (P=0.007). Microarray in liver

(n=10) identified down-regulation of genes critical to intra-hepatic T-cell

signalling associated with GBV-C. Quantitative RT-PCR in liver (n=13) confirmed

down-regulation of lymphocyte-specific protein tyrosine kinase (LCK) (P=0.02)

and docking protein 2 (P=0.04). No differences in expression of theses genes

were seen in PBMCs (n=22) according to GBV-C status. Hepatic expression of the

LCK protein by immunohistochemistry (n=36) was decreased in CD3-positive T-cells

within portal tracts associated with GBV-C (P=0.003). This remained significant

in multivariate analysis controlling for hepatic fibrosis and inflammation

(P=0.027). No differences were seen in plasma cytokine concentrations (n=25) or

ex-vivo peripheral T-cell responses (n=13) versus GBV-C status.

CONCLUSIONS: GBV-C infection is associated with down-regulation of critical

genes involved in intra-hepatic T-cell signaling in HCV/HIV co-infection. This

may be relevant to the pathogenesis of reduced HCV-related liver disease in HIV

PMID: 21266183 [PubMed - as supplied by publisher]

January 29, 2011