Structural basis for germline antibody recognition of HIV-1 immunogens.

Autor:	Scharf L; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States., West AP; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States., Sievers SA; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States., Chen C; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States., Jiang S; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States., Gao H; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States., Gray MD; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States., McGuire AT; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Scheid JF; Laboratory of Molecular Immunology, The Rockefeller University, New York, United States., Nussenzweig MC; Laboratory of Molecular Immunology, The Rockefeller University, New York, United States.; Howard Hughes Medical Institute, The Rockefeller University, New York, United States., Stamatatos L; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Bjorkman PJ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2016 Mar 21; Vol. 5. Date of Electronic Publication: 2016 Mar 21.
DOI:	10.7554/eLife.13783
Abstrakt:	Efforts to elicit broadly neutralizing antibodies (bNAbs) against HIV-1 require understanding germline bNAb recognition of HIV-1 envelope glycoprotein (Env). The VRC01-class bNAb family derived from the VH1-2*02 germline allele arose in multiple HIV-1-infected donors, yet targets the CD4-binding site on Env with common interactions. Modified forms of the 426c Env that activate germline-reverted B cell receptors are candidate immunogens for eliciting VRC01-class bNAbs. We present structures of germline-reverted VRC01-class bNAbs alone and complexed with 426c-based gp120 immunogens. Germline bNAb-426c gp120 complexes showed preservation of VRC01-class signature residues and gp120 contacts, but detectably different binding modes compared to mature bNAb-gp120 complexes. Unlike typical antibody-antigen interactions, VRC01-class germline antibodies exhibited preformed antigen-binding conformations for recognizing immunogens. Affinity maturation introduced substitutions increasing induced-fit recognition and electropositivity, potentially to accommodate negatively-charged complex-type N-glycans on gp120. These results provide general principles relevant to the unusual evolution of VRC01-class bNAbs and guidelines for structure-based immunogen design.
Databáze:	MEDLINE
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