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Thomas Morrison, Julie M Fox, Alison W Ashbrook, Nick A May, Kristin M Schroeder, Raul M Torres, Terence S Dermody, Michael S Diamond, David W Hawman, Pathogenic chikungunya virus evades B cell responses to establish persistence, The Journal of Immunology, Volume 196, Issue 1_Supplement, May 2016, Page 147.12, https://doi.org/10.4049/jimmunol.196.Supp.147.12
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Abstract
Chikungunya virus (CHIKV) causes large outbreaks of acute and chronic musculoskeletal disease. To investigate mechanisms of CHIKV clearance and persistence, we performed studies in mice with an attenuated CHIKV strain (181/25) and its pathogenic parent strain (AF15561). Whereas AF15561 infection of WT mice resulted in viral persistence in joint-associated tissue, 181/25 was cleared within 4 weeks. In contrast to WT mice, 181/25 infection of Rag1−/−mice resulted in viral persistence in joint tissue at levels similar to that detected in AF15561-infected Rag1−/− mice, suggesting an important role for adaptive immunity in the clearance of 181/25 infection. Indeed, 181/25 infection of B cell-deficient μMT mice or B cell receptor transgenic mice that cannot produce virus-specific antibody resulted in viral persistence that was equivalent to AF15561-infected WT and immunodeficient mice. In WT mice, 181/25 infection resulted in a higher quality neutralizing antibody response at early times post-infection. In addition, detailed mapping studies demonstrated that the amino acid at position 82 in the A domain of the E2 glycoprotein influenced clearance and serum neutralization of CHIKV. Neutralization assays revealed that inhibition of AF15561 by monoclonal antibodies specifically targeting E2 domain B was impaired relative to that observed with 181/25. Collectively, our data suggest that virus-specific antibody responses contribute to the clearance of 181/25 infection and that AF15561 evades this response by minimizing the impact of B domain neutralizing antibodies to establish persistent infection.
