Human infants mount relatively poor quality antibody responses of low titer to primary viral infections such as rotavirus. It has been speculated that the B cell repertoire of infants is limited because of residual fetal-like constrained VH usage, and that this is a principal mechanism underlying the poor antibody response of infants to foreign antigens early in life. If this is so, then attempts to vaccinate infants at very young ages with novel antigens complexed with adjuvants that enhance antigen presentation or T cell help are unlikely to be effective. Therefore it is critical to determine if the B cell repertoire in infants is functionally mature. The central hypothesis of this proposal is that infant B cell repertoires are sufficiently diversified for mature virus-specific responses, but lack somatic mutations.
Three specific aims are proposed:
SPECIFIC AIM 1. To determine the genetic basis for binding of infant and adult RV-specific Abs, using detailed analysis of variable gene regions induced by infection. We will identify the immunodominant variable genes used to make RV-specific Abs, and will determine whether infants use the same Ab variable genes as adults.
SPECIFIC AIM 2. To identify the structural determinants of optimal binding of anti-RV Abs. We will test the hypothesis that infant Abs using unmutated immunodominant VH segments in the RV Ab response (such as VH1-46) bind to RV with low affinity, but naturally occurring mutated adult VH1-46 Abs bind RV with high affinity.
SPECIFIC AIM 3. To test the hypothesis that amino acid residues in mutated adult Abs that contribute to increased affinity of interaction of VP7 Abs confer a higher activity for virus neutralization. This work addresses whether increases in affinity at the biochemical level of Ag-Ab interaction increase functional activity (potency) of Abs. This work will demonstrate that infant B cell repertoires used to make specific antiviral responses, in contrast to much previous speculation, are much closer in character to adult repertoires than fetal repertoires. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057933-02
Application #
6899314
Study Section
Special Emphasis Panel (ZRG1-SSS-F (02))
Program Officer
Berard, Diana S
Project Start
2004-06-15
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$377,500
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Kallewaard, Nicole L; McKinney, Brett A; Gu, Yingqi et al. (2008) Functional maturation of the human antibody response to rotavirus. J Immunol 180:3980-9
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Bowen, Amber L; Tian, Cuixia; LaFleur, Bonnie J et al. (2006) Transcriptional control of activation-induced cytidine deaminase and error-prone DNA polymerases is functionally mature in the B cells of infants at birth. Hum Immunol 67:43-6
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Weitkamp, Jorn-Hendrik; Kallewaard, Nicole L; Bowen, Amber L et al. (2005) VH1-46 is the dominant immunoglobulin heavy chain gene segment in rotavirus-specific memory B cells expressing the intestinal homing receptor alpha4beta7. J Immunol 174:3454-60
Weitkamp, Jorn-Hendrik; Lafleur, Bonnie J; Greenberg, Harry B et al. (2005) Natural evolution of a human virus-specific antibody gene repertoire by somatic hypermutation requires both hotspot-directed and randomly-directed processes. Hum Immunol 66:666-76