Antibodies VRC01 and 10E8 neutralize HIV-1 with high breadth and potency even with ig-framework regions substantially reverted to germline

Ivelin S. Georgiev, Rebecca S. Rudicell, Kevin O. Saunders, Wei Shi, Tatsiana Kirys, Krisha McKee, Sijy O'Dell, Gwo Yu Chuang, Zhi Yong Yang, Gilad Ofek, Mark Connors, John R. Mascola, Gary J. Nabel, Peter D. Kwong

Research output: Contribution to journalArticle

Abstract

Abs capable of effectively neutralizing HIV-1 generally exhibit very high levels of somatic hypermutation, both in their CDR and framework-variable regions. In many cases, full reversion of the Ab-framework mutations back to germline results in substantial to complete loss of HIV-1-neutralizing activity. However, it has been unclear whether all or most of the observed framework mutations would be necessary or whether a small subset of these mutations might be sufficient for broad and potent neutralization. To address this issue and to explore the dependence of neutralization activity on the level of somatic hypermutation in the Ab framework, we applied a computationally guided framework-reversion procedure to two broadly neutralizing anti-HIV-1 Abs, VRC01 and 10E8, which target two different HIV-1 sites of vulnerability. Ab variants in which up to 78% (38 of 49 for VRC01) and 89% (31 of 35 for 10E8) of framework mutations were reverted to germline retained breadth and potency within 3-fold of the mature Abs when evaluated on a panel of 21 diverse viral strains. Further, a VRC01 variant with an ~50% framework-reverted L chain showed a 2-fold improvement in potency over the mature Ab. Our results indicate that only a small number of Abframework mutations may be sufficient for high breadth and potency of HIV-1 neutralization by Abs VRC01 and 10E8. Partial framework revertants of HIV-1 broadly neutralizing Abs may present advantages over their highly mutated counterparts as Ab therapeutics and as targets for immunogen design.

Original languageEnglish (US)
Pages (from-to)1100-1106
Number of pages7
JournalJournal of Immunology
Volume192
Issue number3
DOIs
StatePublished - Feb 1 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology

Cite this

Georgiev, I. S., Rudicell, R. S., Saunders, K. O., Shi, W., Kirys, T., McKee, K., O'Dell, S., Chuang, G. Y., Yang, Z. Y., Ofek, G., Connors, M., Mascola, J. R., Nabel, G. J., & Kwong, P. D. (2014). Antibodies VRC01 and 10E8 neutralize HIV-1 with high breadth and potency even with ig-framework regions substantially reverted to germline. Journal of Immunology, 192(3), 1100-1106. https://doi.org/10.4049/jimmunol.1302515