adapted HCV in chimps

adapted HCV in chimps - Mutations that permit efficient...

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Mutations that permit efficient replication of hepatitis C virus RNA in Huh-7 cells prevent productive replication in chimpanzees Jens Bukh* , Thomas Pietschmann ‡§ , Volker Lohmann ‡§ , Nicole Krieger ‡§ , Kristina Faulk*, Ronald E. Engle*, Sugantha Govindarajan , Max Shapiro i , Marisa St. Claire i , and Ralf Bartenschlager ‡§ *Hepatitis Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Institute for Virology, Johannes Gutenberg University, Mainz 55131, Germany; § Department of Molecular Virology, Institute of Hygiene, University of Heidelberg, Heidelberg 69120, Germany; Liver Research Laboratory, Rancho Los Amigos Medical Center, Downey, CA 90242; and i Bioqual Incorporated, Rockville, MD 20850 Communicated by Robert H. Purcell, National Institutes of Health, Bethesda, MD, September 3, 2002 (received for review August 6, 2002) The development of a subgenomic replicon derived from the hepatitis C virus (HCV) strain Con1 enabled the study of viral RNA replication in Huh-7 cells. The level of replication of replicons, as well as full-length Con1 genomes, increased signi±cantly by a combination of two adaptive mutations in NS3 (E1202G and T1280I) and a single mutation in NS5A (S2197P). However, these cell culture-adaptive mutations in²uenced in vivo infectivity. After intrahepatic transfection of chimpanzees, the wild-type Con1 ge- nome was infectious and produced viral titers similar to those produced by other infectious HCV clones. Repeated independent transfections with RNA transcripts of a Con1 genome containing the three adaptive mutations failed to achieve active HCV infec- tion. Furthermore, although a chimpanzee transfected with RNA transcripts of a Con1 genome with only the NS5A mutation became infected, this mutation was detected only in virus genomes recov- ered from serum at day 4; viruses recovered at day 7 had a reversion back to the original Con1 sequence. Our study demon- strates that mutations that are adaptive for replication of HCV in cell culture may be highly attenuating in vivo . H epatitis C virus (HCV) is an enveloped virus with a positive- strand RNA genome (1). Worldwide, more than 100 million people are persistently infected with HCV (2). Infected individ- uals are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. In a subset of infected individuals it is possible to eliminate the infection by therapy with IFN and ribavirin (3, 4). Yet, for the development of vaccines or new therapeutics for HCV, it is of great importance to develop cell culture systems to replicate and propagate HCV. The recent construction of a subgenomic replicon, capable of replication in Huh-7 cells, might represent a first step in achieving this goal (5).
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This note was uploaded on 07/12/2011 for the course BIO 620 taught by Professor Hardy during the Spring '11 term at University of Florida.

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adapted HCV in chimps - Mutations that permit efficient...

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