Differences in Allelic Frequency and CDRH3 Region Limit the Engagement of HIV Env Immunogens by Putative VRC01 Neutralizing Antibody Precursors.
Elicitation of broadly neutralizing antibodies remains a long-standing goal of HIV vaccine research. Although such antibodies can arise during HIV-1 infection, gaps in our knowledge of their germline, pre-immune precursor forms, as well as on their interaction with viral Env, limit our ability to elicit them through vaccination. Studies of broadly neutralizing antibodies from the VRC01-class provide insight into progenitor B cell receptors (BCRs) that could develop into this class of antibodies. Here, we employed high-throughput heavy chain variable region (VH)/light chain variable region (VL) deep sequencing, combined with biophysical, structural, and modeling antibody analyses, to interrogate circulating potential VRC01-progenitor BCRs in healthy individuals. Our study reveals that not all humans are equally predisposed to generate VRC01-class antibodies, not all predicted progenitor VRC01-expressing B cells can bind to Env, and the CDRH3 region of germline VRC01 antibodies influence their ability to recognize HIV-1. These findings will be critical to the design of optimized immunogens that should consider CDRH3 interactions.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Christina
C
Yacoob
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA; Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: mpancera@fredhutch.org.
Marie
M
Pancera
Center for Infectious Disease Research, 307 Westlake Avenue North #500, Seattle, WA 98109, USA.
Vladimir
V
Vigdorovich
Center for Infectious Disease Research, 307 Westlake Avenue North #500, Seattle, WA 98109, USA.
Brian G
BG
Oliver
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Jolene A
JA
Glenn
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Junli
J
Feng
Center for Infectious Disease Research, 307 Westlake Avenue North #500, Seattle, WA 98109, USA.
D Noah
DN
Sather
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Andrew T
AT
McGuire
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA; Department of Global Health, University of Washington, 1410 Northeast Campus Parkway, Seattle, WA 98195, USA. Electronic address: lstamata@fredhutch.org.
Leonidas
L
Stamatatos
D000483:Alleles; D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics*; D005854:Germ Cells / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
D057134:Antibodies, Neutralizing; D022801:Complementarity Determining Regions; D007075:Immunoglobulin M; D054299:env Gene Products, Human Immunodeficiency Virus
CDRH3; HIV; VRC01; broadly neutralizing antibodies; germline; human alleles; human antibodies