Human Peripheral Blood Antibodies with Long HCDR3s Are Established Primarily at Original Recombination Using a Limited Subset of Germline Genes
Open Access
- 9 May 2012
- journal article
- clinical trial
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (5), e36750
- https://doi.org/10.1371/journal.pone.0036750
Abstract
A number of antibodies that efficiently neutralize microbial targets contain long heavy chain complementarity determining region 3 (HCDR3) loops. For HIV, several of the most broad and potently neutralizing antibodies have exceptionally long HCDR3s. Two broad potently neutralizing HIV-specific antibodies, PG9 and PG16, exhibit secondary structure. Two other long HCDR3 antibodies, 2F5 and 4E10, protect against mucosal challenge with SHIV. Induction of such long HCDR3 antibodies may be critical to the design of an effective vaccine strategy for HIV and other pathogens, however it is unclear at present how to induce such antibodies. Here, we present genetic evidence that human peripheral blood antibodies containing long HCDR3s are not primarily generated by insertions introduced during the somatic hypermutation process. Instead, they are typically formed by processes occurring as part of the original recombination event. Thus, the response of B cells encoding antibodies with long HCDR3s results from selection of unusual clones from the naïve repertoire rather than through accumulation of insertions. These antibodies typically use a small subset of D and J gene segments that are particularly suited to encoding long HCDR3s, resulting in the incorporation of highly conserved genetic elements in the majority of antibody sequences encoding long HCDR3s.Keywords
This publication has 51 references indexed in Scilit:
- Broad neutralization coverage of HIV by multiple highly potent antibodiesNature, 2011
- Structural Analysis of Human and Macaque mAbs 2909 and 2.5B: Implications for the Configuration of the Quaternary Neutralizing Epitope of HIV-1 gp120Structure, 2011
- Variable Loop Glycan Dependency of the Broad and Potent HIV-1-Neutralizing Antibodies PG9 and PG16Journal of Virology, 2010
- Scaffolding to build a rational vaccine design strategyProceedings of the National Academy of Sciences of the United States of America, 2010
- Rational antibody-based HIV-1 vaccine design: current approaches and future directionsCurrent Opinion in Immunology, 2010
- Structure and function of broadly reactive antibody PG16 reveal an H3 subdomain that mediates potent neutralization of HIV-1Proceedings of the National Academy of Sciences of the United States of America, 2010
- Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine TargetScience, 2009
- IMGT(R), the international ImMunoGeneTics information system(R)Nucleic Acids Research, 2008
- IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysisNucleic Acids Research, 2008
- Forced usage of positively charged amino acids in immunoglobulin CDR-H3 impairs B cell development and antibody productionThe Journal of Experimental Medicine, 2006