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Journal of Virology, February 2004, p. 1575-1581, Vol. 78, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.3.1575-1581.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Cross-Genotype Immunity to Hepatitis C Virus

Robert E. Lanford,1* Bernadette Guerra,1 Deborah Chavez,1 Catherine Bigger,1 Kathleen M. Brasky,2 Xiao-Hong Wang,3 Stuart C. Ray,3 and David L. Thomas3

Departments of Virology and Immunology,1 Comparative Medicine, Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, Texas 78227,2 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 212053

Received 11 July 2003/ Accepted 13 October 2003

Recent studies in humans and chimpanzees suggest that immunity can be induced to diminish the incidence of chronic hepatitis C virus (HCV) infection. However, the immunity that promotes viral recovery is poorly understood, and whether the breadth of this adaptive immunity is sufficient to overcome the substantial intergenotype antigenic diversity represents a final obstacle to demonstrating the feasibility of vaccine development. Here we demonstrate that recovery from a genotype 1 HCV infection protects chimpanzees against infection with representatives of other genotypes that exhibit up to 30% divergence at the amino acid level, including challenges with genotype 4, a mixture of genotypes 2 and 3, and a complex inoculum containing genotypes 1, 2, 3, and 4. In each instance, the level and duration of viremia were markedly reduced in comparison to the primary infection in the same animal. The data indicate that epitopes conserved between genotypes must play an essential role in immunity. The inocula used in the rechallenge studies induced typical primary infection profiles in naïve chimpanzees. Rechallenge infections were associated with rapid increases in the intrahepatic transcripts of interferon-stimulated genes, even in animals exhibiting apparent sterilizing immunity. Protective immunity was often associated with an early increase in gamma interferon transcripts in the liver and increases in intrahepatic transcripts of Mig, a T-cell chemokine that is a gamma interferon response gene. These studies are the first to show that cross-genotype immunity can be induced to HCV, demonstrating the feasibility of developing a vaccine protective against all HCV strains.

* Corresponding author. Mailing address: Department of Virology and Immunology, Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, 7620 N.W. Loop 410, San Antonio, TX 78227. Phone: (210) 258-9445. Fax: (210) 670-3329. E-mail: rlanford{at}icarus.sfbr.org.

Journal of Virology, February 2004, p. 1575-1581, Vol. 78, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.3.1575-1581.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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