Immune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10.

TitleImmune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10.
Publication TypeJournal Article
Year of Publication2013
AuthorsDoyle-Cooper C, Hudson KE, Cooper AB, Ota T, Skog P, Dawson PE, Zwick MB, Schief WR, Burton DR, Nemazee D
JournalJ Immunol
Volume191
Issue6
Pagination3186-91
Date Published09/15/2013
ISSN1550-6606
KeywordsAIDS Vaccines, Animals, Antibodies, Neutralizing, B-Lymphocytes, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Gene Knock-In Techniques, HIV Antibodies, HIV Antigens, HIV Envelope Protein gp120, HIV Envelope Protein gp41, Immune Tolerance, Immunoglobulin Heavy Chains, Immunoglobulin Light Chains, Mice, Mice, Inbred C57BL, Mice, Transgenic
Abstract

A major goal of HIV research is to develop vaccines reproducibly eliciting broadly neutralizing Abs (bNAbs); however, this has proved to be challenging. One suggested explanation for this difficulty is that epitopes seen by bNAbs mimic self, leading to immune tolerance. We generated knock-in mice expressing bNAb 4E10, which recognizes the membrane proximal external region of gp41. Unlike b12 knock-in mice, described in the companion article (Ota et al. 2013. J. Immunol. 191: 3179-3185), 4E10HL mice were found to undergo profound negative selection of B cells, indicating that 4E10 is, to a physiologically significant extent, autoreactive. Negative selection occurred by various mechanisms, including receptor editing, clonal deletion, and receptor downregulation. Despite significant deletion, small amounts of IgM and IgG anti-gp41 were found in the sera of 4E10HL mice. On a Rag1⁻/⁻ background, 4E10HL mice had virtually no serum Ig of any kind. These results are consistent with a model in which B cells with 4E10 specificity are counterselected, raising the question of how 4E10 was generated in the patient from whom it was isolated. This represents the second example of a membrane proximal external region-directed bNAb that is apparently autoreactive in a physiological setting. The relative conservation in HIV of the 4E10 epitope might reflect the fact that it is under less intense immunological selection as a result of B cell self-tolerance. The safety and desirability of targeting this epitope by a vaccine is discussed in light of the newly described bNAb 10E8.

DOI10.4049/jimmunol.1301285
Alternate JournalJ. Immunol.
PubMed ID23940276
PubMed Central IDPMC3773228
Grant ListR01 AI059714 / AI / NIAID NIH HHS / United States
R01 AI073148 / AI / NIAID NIH HHS / United States
R01AI059714 / AI / NIAID NIH HHS / United States
R01AI073148 / AI / NIAID NIH HHS / United States
R56 AI073148 / AI / NIAID NIH HHS / United States
U01AI078224 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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