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Comprehensive antigenic map of a cleaved soluble HIV-1 envelope trimer.

Derking R, Ozorowski G, Sliepen K, Yasmeen A, Cupo A, Torres JL, Julien JP, Lee JH, van Montfort T, de Taeye SW, Connors M, Burton DR, Wilson IA, Klasse PJ, Ward AB, Moore JP, Sanders RW - PLoS Pathog. (2015)

Bottom Line: It also identifies the relationships among these clusters.We further demonstrate that bNAb binding can be complex, often affecting several other areas of the trimer surface beyond the epitope.This extensive analysis of the antigenic structure and the epitope interrelationships of the Env trimer should aid in design of both bNAb-based therapies and vaccines intended to induce bNAbs.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

ABSTRACT
The trimeric envelope (Env) spike is the focus of vaccine design efforts aimed at generating broadly neutralizing antibodies (bNAbs) to protect against HIV-1 infection. Three recent developments have facilitated a thorough investigation of the antigenic structure of the Env trimer: 1) the isolation of many bNAbs against multiple different epitopes; 2) the generation of a soluble trimer mimic, BG505 SOSIP.664 gp140, that expresses most bNAb epitopes; 3) facile binding assays involving the oriented immobilization of tagged trimers. Using these tools, we generated an antigenic map of the trimer by antibody cross-competition. Our analysis delineates three well-defined epitope clusters (CD4 binding site, quaternary V1V2 and Asn332-centered oligomannose patch) and new epitopes at the gp120-gp41 interface. It also identifies the relationships among these clusters. In addition to epitope overlap, we defined three more ways in which antibodies can cross-compete: steric competition from binding to proximal but non-overlapping epitopes (e.g., PGT151 inhibition of 8ANC195 binding); allosteric inhibition (e.g., PGT145 inhibition of 1NC9, 8ANC195, PGT151 and CD4 binding); and competition by reorientation of glycans (e.g., PGT135 inhibition of CD4bs bNAbs, and CD4bs bNAb inhibition of 8ANC195). We further demonstrate that bNAb binding can be complex, often affecting several other areas of the trimer surface beyond the epitope. This extensive analysis of the antigenic structure and the epitope interrelationships of the Env trimer should aid in design of both bNAb-based therapies and vaccines intended to induce bNAbs.

No MeSH data available.


Related in: MedlinePlus

Four mechanisms of bNAb binding interference.(1) Direct overlap of epitopes; (2) Steric inhibition; (3) Allosteric inhibition; (4) Reorientation of glycans. See text for details.
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ppat.1004767.g007: Four mechanisms of bNAb binding interference.(1) Direct overlap of epitopes; (2) Steric inhibition; (3) Allosteric inhibition; (4) Reorientation of glycans. See text for details.

Mentions: Using a bNAb cross-competition ELISA, supported by SPR data and structural analyses, we have defined the steric and allosteric relationships among the known antigenic sites on the HIV-1 Env trimer. We have also identified four mechanisms by which bNAbs can interfere with one another’s binding (Fig. 7): 1) direct overlap of epitopes (many examples); 2) steric inhibition (PGT151 inhibition of 8ANC195); 3) allosteric inhibition (PGT145 inhibition of 1NC9, 8ANC195, PGT151 or CD4); 4) glycan reorientation (PGT135/PGT136 inhibition of CD4bs bNAbs, and CD4bs bNAb inhibition of 8ANC195). Whether competition between bNAbs is or is not reciprocal can also be influenced by both binding affinity (competition in ELISA is likely to be influenced substantially by bNAb off-rates) and stoichiometry (whether 1, 2 or 3 copies of a bNAb bind the trimer). Overall, based on our current observations, the binding of bNAbs to the trimer can involve local remodeling of loops or glycans, as well as triggering long-distance allosteric effects.


Comprehensive antigenic map of a cleaved soluble HIV-1 envelope trimer.

Derking R, Ozorowski G, Sliepen K, Yasmeen A, Cupo A, Torres JL, Julien JP, Lee JH, van Montfort T, de Taeye SW, Connors M, Burton DR, Wilson IA, Klasse PJ, Ward AB, Moore JP, Sanders RW - PLoS Pathog. (2015)

Four mechanisms of bNAb binding interference.(1) Direct overlap of epitopes; (2) Steric inhibition; (3) Allosteric inhibition; (4) Reorientation of glycans. See text for details.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4373910&req=5

ppat.1004767.g007: Four mechanisms of bNAb binding interference.(1) Direct overlap of epitopes; (2) Steric inhibition; (3) Allosteric inhibition; (4) Reorientation of glycans. See text for details.
Mentions: Using a bNAb cross-competition ELISA, supported by SPR data and structural analyses, we have defined the steric and allosteric relationships among the known antigenic sites on the HIV-1 Env trimer. We have also identified four mechanisms by which bNAbs can interfere with one another’s binding (Fig. 7): 1) direct overlap of epitopes (many examples); 2) steric inhibition (PGT151 inhibition of 8ANC195); 3) allosteric inhibition (PGT145 inhibition of 1NC9, 8ANC195, PGT151 or CD4); 4) glycan reorientation (PGT135/PGT136 inhibition of CD4bs bNAbs, and CD4bs bNAb inhibition of 8ANC195). Whether competition between bNAbs is or is not reciprocal can also be influenced by both binding affinity (competition in ELISA is likely to be influenced substantially by bNAb off-rates) and stoichiometry (whether 1, 2 or 3 copies of a bNAb bind the trimer). Overall, based on our current observations, the binding of bNAbs to the trimer can involve local remodeling of loops or glycans, as well as triggering long-distance allosteric effects.

Bottom Line: It also identifies the relationships among these clusters.We further demonstrate that bNAb binding can be complex, often affecting several other areas of the trimer surface beyond the epitope.This extensive analysis of the antigenic structure and the epitope interrelationships of the Env trimer should aid in design of both bNAb-based therapies and vaccines intended to induce bNAbs.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

ABSTRACT
The trimeric envelope (Env) spike is the focus of vaccine design efforts aimed at generating broadly neutralizing antibodies (bNAbs) to protect against HIV-1 infection. Three recent developments have facilitated a thorough investigation of the antigenic structure of the Env trimer: 1) the isolation of many bNAbs against multiple different epitopes; 2) the generation of a soluble trimer mimic, BG505 SOSIP.664 gp140, that expresses most bNAb epitopes; 3) facile binding assays involving the oriented immobilization of tagged trimers. Using these tools, we generated an antigenic map of the trimer by antibody cross-competition. Our analysis delineates three well-defined epitope clusters (CD4 binding site, quaternary V1V2 and Asn332-centered oligomannose patch) and new epitopes at the gp120-gp41 interface. It also identifies the relationships among these clusters. In addition to epitope overlap, we defined three more ways in which antibodies can cross-compete: steric competition from binding to proximal but non-overlapping epitopes (e.g., PGT151 inhibition of 8ANC195 binding); allosteric inhibition (e.g., PGT145 inhibition of 1NC9, 8ANC195, PGT151 and CD4 binding); and competition by reorientation of glycans (e.g., PGT135 inhibition of CD4bs bNAbs, and CD4bs bNAb inhibition of 8ANC195). We further demonstrate that bNAb binding can be complex, often affecting several other areas of the trimer surface beyond the epitope. This extensive analysis of the antigenic structure and the epitope interrelationships of the Env trimer should aid in design of both bNAb-based therapies and vaccines intended to induce bNAbs.

No MeSH data available.


Related in: MedlinePlus