Pathogenic Chikungunya Virus Evades B Cell Responses to Establish Persistence

• A highly conserved glycine at E2 residue 82 promotes CHIKV persistence in joints
• E2-R82 promotes viral clearance from joints of WT, but not B-cell-deficient, mice
• E2-R82 enhances CHIKV neutralization by human and mouse polyclonal antibodies
• Pathogenic CHIKV strains are resistant to neutralization by E2 B domain antibodies

SummaryChikungunya 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.

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