Scientific Publications
- PMID: 24550318
- Title: Vaccine elicited primate antibodies use a distinct approach to the HIV 1 primary receptor binding site informing vaccine redesign
- Abstract: HIV-1 neutralization requires Ab accessibility to the functional envelope glycoprotein (Env) spike. We recently reported the isolation of previously unidentified vaccine-elicited, CD4 binding site (CD4bs)-directed mAbs from rhesus macaques immunized with soluble Env trimers, indicating that this region is immunogenic in the context of subunit vaccination. To elucidate the interaction of the trimer-elicited mAbs with gp120 and their insufficient interaction with the HIV-1 primary isolate spike, we crystallized the Fab fragments of two mAbs, GE136 and GE148. Alanine scanning of their complementarity-determining regions, coupled with epitope scanning of their epitopes on gp120, revealed putative contact residues at the Ab/gp120 interface. Docking of the GE136 and GE148 Fabs to gp120, coupled with EM reconstructions of these nonbroadly neutralizing mAbs (non-bNAbs) binding to gp120 monomers and EM modeling to well-ordered trimers, suggested Ab approach to the CD4bs by a vertical angle of access relative to the more lateral mode of interaction used by the CD4bs-directed bNAbs VRC01 and PGV04. Fitting the structures into the available cryo-EM native spike density indicated clashes between these two vaccine-elicited mAbs and the topside variable region spike cap, whereas the bNAbs duck under this quaternary shield to access the CD4bs effectively on primary HIV isolates. These results provide a structural basis for the limited neutralizing breadth observed by current vaccine-induced, CD4bs-directed Abs and highlight the need for better ordered trimer immunogens. The analysis presented here therefore provides valuable information to guide HIV-1 vaccine immunogen redesign.
- Date: 1970-08-21
- Year: 2014
- Journal: Proc. Natl. Acad. Sci. U.S.A.
- PMID Author: Tran K, Poulsen C, Guenaga J, de Val N, de Val Alda N, Wilson R, Sundling C, Li Y, Stanfield RL, Wilson IA, Ward AB, Karlsson Hedestam GB, Wyatt RT
- PMC Link #: PMC3932900
Vaccine elicited primate antibodies use a distinct approach to the HIV 1 primary receptor binding site informing vaccine redesign
Vaccine-elicited primate antibodies use a distinct approach to the HIV-1 primary receptor binding site informing vaccine redesign. Proc. Natl. Acad. Sci. U.S.A. 2014;111(7):E738-47 doi: 10.1073/pnas.1319512111
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