title: Pathogenic Chikungunya Virus Evades B Cell Responses to Establish Persistence.
abstract: Chikungunya virus (CHIKV) and related alphaviruses cause epidemics of acute and chronic musculoskeletal disease. To investigate the mechanisms underlying the failure of immune clearance of CHIKV, we studied mice infected with an attenuated CHIKV strain (181/25) and the pathogenic parental strain (AF15561), which differ by five amino acids. Whereas AF15561 infection of wild-type mice results in viral persistence in joint tissues, 181/25 is cleared. In contrast, 181/25 infection of μMT mice lacking mature B cells results in viral persistence in joint tissues, suggesting that virus-specific antibody is required for clearance of infection. Mapping studies demonstrated that a highly conserved glycine at position 82 in the A domain of the E2 glycoprotein impedes clearance and neutralization of multiple CHIKV strains. Remarkably, murine and human antibodies targeting E2 domain B failed to neutralize pathogenic CHIKV strains efficiently. Our data suggest that pathogenic CHIKV strains evade E2 domain-B-neutralizing antibodies to establish persistence.
authors.affiliation: Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO 80045, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Hawman
authors.affiliation: Department of Medicine, School of Medicine, Washington University, Saint Louis, MO 63110, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Fox
authors.affiliation: Department of Pediatrics, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA; Elizabeth B. Lamb Center for Pediatric Research, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Alison W
authors.initials: AW
authors.lastname: Ashbrook
authors.affiliation: Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: May
authors.affiliation: Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Kristin M S
authors.initials: KMS
authors.lastname: Schroeder
authors.affiliation: Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Raul M
authors.initials: RM
authors.lastname: Torres
authors.affiliation: Department of Pediatrics, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
authors.affiliation: Department of Pediatrics, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA; Elizabeth B. Lamb Center for Pediatric Research, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Terence S
authors.initials: TS
authors.lastname: Dermody
authors.affiliation: Department of Medicine, School of Medicine, Washington University, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, School of Medicine, Washington University, Saint Louis, MO 63110, USA; Department of Pathology & Immunology, School of Medicine, Washington University, Saint Louis, MO 63110, USA; Center for Human Immunology and Immunotherapy Programs and School of Medicine, Washington University, Saint Louis, MO 63110, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.affiliation: Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO 80045, USA. Electronic address: thomas.morrison@ucdenver.edu.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Morrison
mesh_terms: D000596:Amino Acids / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D065632:Chikungunya Fever / Q000276:immunology*; D002646:Chikungunya virus / Q000276:immunology*; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D014759:Viral Envelope Proteins / Q000276:immunology
chemical_list: D000596:Amino Acids; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D006023:Glycoproteins; D014759:Viral Envelope Proteins