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Journal of Virology, April 2009, p. 3104-3114, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.01679-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Internal Initiation Stimulates Production of p8 Minicore, a Member of a Newly Discovered Family of Hepatitis C Virus Core Protein Isoforms{triangledown}

Francis J. Eng,1 Jose L. Walewski,1 Arielle L. Klepper,1 Sarah L. Fishman,1 Suresh M. Desai,2 Laura K. McMullan,3,{dagger} Matthew J. Evans,3,{ddagger} Charles M. Rice,3 and Andrea D. Branch1*

Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York 10029,1 Abbott Laboratories, Abbott Park, Illinois 60064,2 Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 100213

Received 6 August 2008/ Accepted 28 December 2008

The hepatitis C virus (HCV) core gene is more conserved at the nucleic acid level than is necessary to preserve the sequence of the core protein, suggesting that it contains information for additional functions. We used a battery of anticore antibodies to test the hypothesis that the core gene directs the synthesis of core protein isoforms. Infectious viruses, replicons, and RNA transcripts expressed a p8 minicore containing the C-terminal portion of the p21 core protein and lacking the N-terminal portion. An interferon resistance mutation, U271A, which creates an AUG at codon 91, upregulated p8 expression in Con1 replicons, suggesting that p8 is produced by an internal initiation event and that 91-AUG is the preferred, but not the required, initiation codon. Synthesis of p8 was independent of p21, as shown by the abundant production of p8 from transcripts containing an UAG stop codon that blocked p21 production. Three infectious viruses, JFH-1 (2a core), J6/JFH (2a core), and H77/JFH (1a core), and a bicistronic construct, Bi-H77/JFH, all expressed both p8 and larger isoforms. The family of minicores ranges in size from 8 to 14 kDa. All lack the N-terminal portion of the p21 core. In conclusion, the core gene contains an internal signal that stimulates the initiation of protein synthesis at or near codon 91, leading to the production of p8. Infectious viruses of both genotype 1 and 2 HCV express a family of larger isoforms, in addition to p8. Minicores lack significant portions of the RNA binding domain of p21 core. Studies are under way to determine their functions.

* Corresponding author. Mailing address: Division of Liver Diseases, Mount Sinai School of Medicine, 1425 Madison Ave., Box 11-20, New York, NY 10029. Phone: (212) 659-8371. Fax: (212) 348-3517. E-mail: Andrea.Branch{at}mssm.edu

{triangledown} Published ahead of print on 7 January 2009.

{dagger} Present address: Molecular Section, Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, GA 30333.

{ddagger} Present address: Department of Microbiology, The Mount Sinai School of Medicine, New York, NY 10029.

Journal of Virology, April 2009, p. 3104-3114, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.01679-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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