title: Cross-genotype immunity to hepatitis C virus.
abstract: 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.
authors.affiliation: Department of Virology and Immunology, Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, Texas 78227, USA. rlanford@icarus.sfbr.org
authors.forename: Robert E
authors.initials: RE
authors.lastname: Lanford
authors.forename: Bernadette
authors.initials: B
authors.lastname: Guerra
authors.forename: Deborah
authors.initials: D
authors.lastname: Chavez
authors.forename: Catherine
authors.initials: C
authors.lastname: Bigger
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Brasky
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Wang
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Ray
authors.forename: David L
authors.initials: DL
authors.lastname: Thomas
mesh_terms: D000818:Animals; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D016174:Hepacivirus / Q000145:classification* / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D006526:Hepatitis C / Q000276:immunology* / Q000821:virology; D006801:Humans; D007109:Immunity; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000276:immunology* / Q000821:virology
chemical_list: C080810:CXCL9 protein, human; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma