Antigenic conservation and immunogenicity of the HIV coreceptor binding site.
Immunogenic, broadly reactive epitopes of the HIV-1 envelope glycoprotein could serve as important targets of the adaptive humoral immune response in natural infection and, potentially, as components of an acquired immune deficiency syndrome vaccine. However, variability in exposed epitopes and a combination of highly effective envelope-cloaking strategies have made the identification of such epitopes problematic. Here, we show that the chemokine coreceptor binding site of HIV-1 from clade A, B, C, D, F, G, and H and circulating recombinant form (CRF)01, CRF02, and CRF11, elicits high titers of CD4-induced (CD4i) antibody during natural human infection and that these antibodies bind and neutralize viruses as divergent as HIV-2 in the presence of soluble CD4 (sCD4). 178 out of 189 (94%) HIV-1-infected patients had CD4i antibodies that neutralized sCD4-pretreated HIV-2 in titers (50% inhibitory concentration) as high as 1:143,000. CD4i monoclonal antibodies elicited by HIV-1 infection also neutralized HIV-2 pretreated with sCD4, and polyclonal antibodies from HIV-1-infected humans competed specifically with such monoclonal antibodies for binding. In vivo, variants of HIV-1 with spontaneously exposed coreceptor binding surfaces were detected in human plasma; these viruses were neutralized directly by CD4i antibodies. Despite remarkable evolutionary diversity among primate lentiviruses, functional constraints on receptor binding create opportunities for broad humoral immune recognition, which in turn serves to constrain the viral quasispecies.
Decker
Julie M
JM
Howard Hughes Institute, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Bibollet-Ruche
Frederic
F
Wei
Xiping
X
Wang
Shuyi
S
Levy
David N
DN
Wang
Wenquan
W
Delaporte
Eric
E
Peeters
Martine
M
Derdeyn
Cynthia A
CA
Allen
Susan
S
Hunter
Eric
E
Saag
Michael S
MS
Hoxie
James A
JA
Hahn
Beatrice H
BH
Kwong
Peter D
PD
Robinson
James E
JE
Shaw
George M
GM
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism*; D000914:Antibodies, Viral / Q000276:immunology / Q000378:metabolism*; D015704:CD4 Antigens / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology; D000939:Epitopes / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D019302:HIV Envelope Protein gp160 / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D015498:HIV-2 / Q000235:genetics / Q000276:immunology; D006801:Humans; D020128:Inhibitory Concentration 50; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009500:Neutralization Tests; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D015704:CD4 Antigens; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D019707:Receptors, Chemokine