title: Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice.
abstract: VRC01-class broadly neutralizing HIV-1 antibodies protect animals from experimental infection and could contribute to an effective vaccine response. Their predicted germline forms (gl) bind Env inefficiently, which may explain why they are not elicited by HIV-1 Env-immunization. Here we show that an optimized Env immunogen can engage multiple glVRC01-class antibodies. Furthermore, this immunogen activates naive B cells expressing the human germline heavy chain of 3BNC60, paired with endogenous mouse light chains in vivo. To address whether it activates B cells expressing the fully humanized gl3BNC60 B-cell receptor (BCR), we immunized mice carrying both the heavy and light chains of gl3BNC60. B cells expressing this BCR display an autoreactive phenotype and fail to respond efficiently to soluble forms of the optimized immunogen, unless it is highly multimerized. Thus, specifically designed Env immunogens can activate naive B cells expressing human BCRs corresponding to precursors of broadly neutralizing HIV-1 antibodies even when the B cells display an autoreactive phenotype.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, PO Box 19024 Seattle, Washington 98109, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: McGuire
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, PO Box 19024 Seattle, Washington 98109, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Gray
authors.affiliation: Laboratory of Molecular Immunology, New York, New York 10065, USA.
authors.forename: Pia
authors.initials: P
authors.lastname: Dosenovic
authors.affiliation: Laboratory of Molecular Immunology, New York, New York 10065, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Gitlin
authors.affiliation: Laboratory of Molecular Immunology, New York, New York 10065, USA.
authors.forename: Natalia T
authors.initials: NT
authors.lastname: Freund
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, PO Box 19024 Seattle, Washington 98109, USA.
authors.forename: John
authors.initials: J
authors.lastname: Petersen
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, PO Box 19024 Seattle, Washington 98109, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Correnti
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, PO Box 19024 Seattle, Washington 98109, USA.
authors.forename: William
authors.initials: W
authors.lastname: Johnsen
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, PO Box 19024 Seattle, Washington 98109, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Kegel
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, PO Box 19024 Seattle, Washington 98109, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Stuart
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, PO Box 19024 Seattle, Washington 98109, USA.
authors.forename: Jolene
authors.initials: J
authors.lastname: Glenn
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, E/CLS-1001, Boston, Massachusetts 02215, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road La Jolla, California 92037, USA.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, 10550 North Torrey Pines Road La Jolla, California 92037, USA.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, 10550 North Torrey Pines Road La Jolla, California 92037, USA.|Ragon Institute of MGH, MIT, and Harvard, 400 Technology Square Cambridge, Massachusetts 02139, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Schief
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, PO Box 19024 Seattle, Washington 98109, USA.
authors.forename: Roland K
authors.initials: RK
authors.lastname: Strong
authors.affiliation: Laboratory of Molecular Immunology, New York, New York 10065, USA.|Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, PO Box 19024 Seattle, Washington 98109, USA.|University of Washington, Department of Global Health, 1510 San Juan Road #310e Seattle, Washington 98195, USA.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D055879:Gene Knock-In Techniques; D015483:HIV Antibodies / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007140:Immunoglobulin Fab Fragments; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007140:Immunoglobulin Fab Fragments; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D011947:Receptors, Antigen, B-Cell; D054299:env Gene Products, Human Immunodeficiency Virus