Elicitation of HIV-1-neutralizing antibodies against the CD4-binding site.
OBJECTIVE
The HIV-1 site of binding for the CD4 receptor has long attracted attention as a potential supersite of vulnerability to antibody-mediated neutralization. We review recent findings related to effective CD4-binding site antibodies isolated from HIV-1-infected individuals and discuss implications for immunogen design.


RESULTS
Highly effective CD4-binding site antibodies such as antibody VRC01 have the ability to neutralize over 90% of circulating HIV-1 strains. Sequence and structural analysis of these antibodies from over half a dozen HIV-1-infected donors reveals remarkable similarity in their ontogenies and their modes of recognition, all of which involve mimicry of CD4 receptor by antibody-heavy chain. Meanwhile, other effective CD4-binding site neutralizers such as antibody CH103 have been shown to utilize a different mode of recognition, with next-generation sequencing of both virus and antibody suggesting co-evolution to drive the development of antibody-neutralization breadth.


CONCLUSIONS
The nexus of information concerning the CD4-binding site and its recognition by human antibodies capable of effective neutralization has expanded remarkably in the last few years. Although barriers are substantial, new insights from donor-serum responses, atomic-level structures of antibody-Env complexes, and next-generation sequencing of B-cell transcripts are invigorating vaccine-design efforts to elicit effective CD4-binding site antibodies.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ivelin S
IS
Georgiev
M
M
Gordon Joyce
Tongqing
T
Zhou
Peter D
PD
Kwong
D057134:Antibodies, Neutralizing / Q000097:blood*; D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism; D015483:HIV Antibodies / Q000097:blood*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D015728:Receptors, HIV / Q000378:metabolism
D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015728:Receptors, HIV; C514793:gp120 protein, Human immunodeficiency virus 1