An HIV-1 Env-Antibody Complex Focuses Antibody Responses to Conserved Neutralizing Epitopes.
Elicitation of broadly neutralizing Ab (bNAb) responses to the conserved elements of the HIV-1 envelope glycoproteins (Env), including the primary receptor CD4 binding site (CD4bs), is a major focus of vaccine development yet to be accomplished. However, a large number of CD4bs-directed bNAbs have been isolated from HIV-1-infected individuals. Comparison of the routes of binding used by the CD4bs-directed bNAbs from patients and the vaccine-elicited CD4bs-directed mAbs indicates that the latter fail to neutralize primary virus isolates because they approach the Env spike with a vertical angle and contact the specific surface residues occluded in the native spike, including the bridging sheet on gp120. To preferentially expose the CD4bs and direct the immune response away from the bridging sheet, resulting in an altered angle of approach, we engineered an immunogen consisting of gp120 core in complex with the prototypic CD4-induced Ab, 17b. This mAb directly contacts the bridging sheet but not the CD4bs. The complex was further stabilized by chemical crosslinking to prevent dissociation. Rabbits immunized with the crosslinked complex displayed earlier affinity maturation, achieving tier 1 virus neutralization compared with animals immunized with gp120 core alone. Immunization with the crosslinked complex induced transient Ab responses with binding specificity similar to the CD4bs-directed bNAbs. mAbs derived from complex-immunized rabbits displayed footprints on gp120 more distal from the bridging sheet as compared with previous vaccine-elicited CD4bs Abs, indicating that Env-Ab complexes effectively dampen immune responses to undesired immunodominant bridging sheet determinants.
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
Yajing
0000-0001-8330-3901
Y
Chen
International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037.
Richard
0000-0002-7718-5344
R
Wilson
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Sijy
S
O'Dell
International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037.
Javier
0000-0003-3912-7482
J
Guenaga
International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037.
Yu
Y
Feng
International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037.
Karen
0000-0002-4393-2073
K
Tran
Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850.
Chi-I
CI
Chiang
International AIDS Vaccine Initiative, Brooklyn, NY 11226; and.
Heather E
HE
Arendt
International AIDS Vaccine Initiative, Brooklyn, NY 11226; and.
Joanne
J
DeStefano
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
John R
JR
Mascola
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.|International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037.|Scripps Center for HIV Vaccine Immunogen Discovery, La Jolla, CA 92037.
Richard T
RT
Wyatt
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; liy@ibbr.umd.edu.|International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037.|Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850.
Yuxing
Y
Li
D016915:AIDS Vaccines / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000276:immunology*; D001665:Binding Sites; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism*; D000939:Epitopes / Q000276:immunology; D006031:Glycosylation; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D007114:Immunization; D008958:Models, Molecular; D011485:Protein Binding; D011817:Rabbits; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000936:Antigen-Antibody Complex; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D054299:env Gene Products, Human Immunodeficiency Virus; C514793:gp120 protein, Human immunodeficiency virus 1