3New Hepatitis C Abstracts

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J Virol. 2011 Sep 14. [Epub ahead of print]

HepG2 cells expressing miR-122 support the entire hepatitis C virus life cycle.

Narbus CM, Israelow B, Sourisseau M, Michta ML, Hopcraft SE, Zeiner GM,

MJ.

Source

Department of Microbiology, Mount Sinai School of Medicine, New York, NY, 10029.

Abstract

The liver specific microRNA, miR-122, is required for efficient hepatitis C

virus (HCV) RNA replication in both cell culture and in vivo. In addition,

nonhepatic cells have been rendered more efficient at supporting this stage of

the HCV life cycle by miR-122 expression. This study investigated how miR-122

influences HCV replication in the miR-122 deficient HepG2 cell line. Expression

of this microRNA in HepG2 cells permitted efficient HCV RNA replication and

infectious virion production. When a missing HCV receptor is also expressed,

these cells efficiently support viral entry and thus the entire HCV life cycle.

PMID: 21917968 [PubMed - as supplied by publisher]

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J Virol. 2011 Sep 14. [Epub ahead of print]

Systems Virology Identifies a Mitochondrial Fatty Acid Oxidation Enzyme,

Dodecenoyl-CoA Delta Isomerase (DCI), Required for HCV Replication and Likely

Pathogenesis.

Rasmussen AL, Diamond DL, McDermott JE, Gao X, Metz TO, Matzke MM, VS,

Belisle SE, Korth MJ, Waters KM, RD, Katze MG.

Source

University of Washington School of Medicine, Department of Microbiology,

Seattle, WA 98195.

Abstract

We previously employed systems biology approaches to identify the mitochondrial

fatty acid oxidation enzyme dodecenoyl-CoA delta isomerase (DCI) as a bottleneck

protein controlling host metabolic reprogramming during hepatitis C virus (HCV)

infection. Here we present the results of studies confirming the importance of

DCI to HCV pathogenesis. Computational models incorporating proteomic data from

HCV patient liver biopsies recapitulated our original predictions regarding DCI

and link HCV-associated alterations in cellular metabolism and liver disease

progression. HCV growth and RNA replication in hepatoma cell lines stably

expressing DCI-targeting short hairpin RNA (shRNA) were abrogated, indicating

that DCI is required for productive infection. Pharmacologic inhibition of fatty

acid oxidation also blocked HCV replication. Production of infectious HCV was

restored by overexpression of a shRNA-resistant DCI allele. These findings

demonstrate the utility of systems biology approaches to gain novel insight into

the biology of HCV infection and identify novel, translationally relevant

therapeutic targets.

PMID: 21917952 [PubMed - as supplied by publisher]

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N Engl J Med. 2011 Sep 15;365(11):1014-24.

Response-guided telaprevir combination treatment for hepatitis C virus

infection.

Sherman KE, Flamm SL, Afdhal NH, DR, Sulkowski MS, Everson GT, Fried MW,

Adler M, Reesink HW, M, Sankoh AJ, Adda N, Kauffman RS, S,

CI, Poordad F; ILLUMINATE Study Team.

Collaborators (75)

Source

Division of Digestive Diseases, University of Cincinnati College of Medicine,

Cincinnati, OH 45267-0595, USA. shermake@...

Abstract

BACKGROUND:

Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often

need 48 weeks of peginterferon-ribavirin treatment for a sustained virologic

response. We designed a noninferiority trial (noninferiority margin, -10.5%) to

compare rates of sustained virologic response among patients receiving two

treatment durations.

METHODS:

We enrolled patients with chronic infection with HCV genotype 1 who had not

previously received treatment. All patients received telaprevir at a dose of 750

mg every 8 hours, peginterferon alfa-2a at a dose of 180 ìg per week, and

ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed

by peginterferon-ribavirin. Patients who had an extended rapid virologic

response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned

after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more

weeks (T12PR48). Patients without an extended rapid virologic response were

assigned to T12PR48.

RESULTS:

Of the 540 patients, a total of 352 (65%) had an extended rapid virologic

response. The overall rate of sustained virologic response was 72%. Among the

322 patients with an extended rapid virologic response who were randomly

assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the

T12PR48 group had a sustained virologic response (absolute difference, 4

percentage points; 95% confidence interval, -2 to 11), establishing

noninferiority. Adverse events included rash (in 37% of patients, severe in 5%)

and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was

based on adverse events in 18% of patients overall, as well as in 1% of patients

(all of whom were randomly assigned) in the T12PR24 group and 12% of the

patients randomly assigned to the T12PR48 group (P<0.001).

CONCLUSIONS:

In this study, among patients with chronic HCV infection who had not received

treatment previously, a regimen of peginterferon-ribavirin for 24 weeks, with

telaprevir for the first 12 weeks, was noninferior to the same regimen for 48

weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended

rapid virologic response achieved in nearly two thirds of patients.

(Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov

number, NCT00758043.).

PMID: 21916639 [PubMed - in process]