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Functional Maturation of the Human Antibody Response to Rotavirus¹

Nicole L. Kallewaard^*, Brett A. McKinney^,, Yingqi Gu^¶, Annie Chen^¶, B. V. Venkataram Prasad^¶ and James E. Crowe, Jr.^2,*,,

^* Departments of Microbiology and Immunology, Department of Mathematics, Department of Pediatrics, and Program in Vaccine Sciences, Vanderbilt University and Vanderbilt University Medical Center, Nashville, TN 37232; and ^¶ Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030

Infant Abs induced by viruses exhibit poor functional activity compared with those of adults. The human B cell response to rotavirus is dominated by use of the V_H1–46 gene segment in both adults and infants, but only adult sequences are highly mutated. We investigated in detail the kinetic, structural, and functional advantage conferred by individual naturally occurring somatic mutations in rotavirus-specific human Abs encoded by the immunodominant V_H1–46 gene segment. Adult Abs achieved enhanced binding through naturally occurring somatic mutations in the H chain CDR2 region that conferred a markedly prolonged off-rate and a desirable increase in antiviral potency. Three-dimensional cryoelectron microscopy studies of Ag-Ab complexes revealed the mechanism of viral inhibition to be the binding of high-affinity Abs at the viral RNA release pore in the double-layer particle. These structure-function studies suggest a molecular basis for the poor quality of Abs made in infancy following virus infection or immunization.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 AI57933 (to J.E.C.) and AI36040 (to B.V.V.P.). N.L.K. was supported by the National Institutes of Health Training Program in Cellular and Molecular Microbiology, T32 AI07611. J.E.C. holds a Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund. Cryo-EM studies were supported by the National Center for Macromolecular Imaging (P41 RR02250).

² Address correspondence and reprint requests to Dr. James E. Crowe, Jr., Vanderbilt University, 1161 21st Avenue South T2220 Medical Center North, Nashville, TN 37232. E-mail address: james.crowe{at}vanderbilt.edu

³ Abbreviations used in this paper: RV, rotavirus; B_max, maximal binding; DLP, double-layer particle; FR, framework region; Fv, fragment variable; HCDR2, H chain CDR2; k_off, rate of dissociation; k_on, rate of association; RSV, respiratory syncytial virus; VP, viral protein.