|Title||Immune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Doyle-Cooper C, Hudson KE, Cooper AB, Ota T, Skog P, Dawson PE, Zwick MB, Schief WR, Burton DR, Nemazee D|
|Keywords||AIDS 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|
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.
|Alternate Journal||J. Immunol.|
|PubMed Central ID||PMC3773228|
|Grant List||R01 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
Immune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10.