The Journal of Experimental Medicine
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Published 2 May 2005. doi:10.1084/jem.20042510
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 9, 1407-1419
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ARTICLE

 Antigenic conservation and immunogenicity of the HIV coreceptor binding site

Julie M. Decker1,2,3, Frederic Bibollet-Ruche1,2,3, Xiping Wei1,2,3, Shuyi Wang1,2,3, David N. Levy1,2,3, Wenquan Wang2,4, Eric Delaporte5, Martine Peeters5, Cynthia A. Derdeyn6,7, Susan Allen8, Eric Hunter6,7, Michael S. Saag2, James A. Hoxie9, Beatrice H. Hahn2,3, Peter D. Kwong10, James E. Robinson11, and George M. Shaw1,2,3

1 Howard Hughes Medical Institute, University of Alabama at Birmingham, Birmingham, AL 35294
2 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294
3 Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294
4 Section of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294
5 Institut de Recherche pour le Developpement, University of Montpellier, Montpellier Cedex 5, France
6 Department of Pathology, Emory University, Atlanta, GA 30329
7 Department of Laboratory Medicine, Emory University, Atlanta, GA 30329
8 International Health, Emory University, Atlanta, GA 30329
9 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
10 Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892
11 Department of Pediatrics, Tulane University Health Sciences Center, New Orleans, LA 70112

CORRESPONDENCE George M. Shaw: gshaw{at}uab.edu

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.

Abbreviations used: CD4i, CD4-induced; CRF, circulating recombinant form; IC50, 50% inhibitory concentration; MPER, membrane-proximal external region; Nab, neutralizing antibody; sCD4, soluble CD4.

J.M. Decker and F. Bibollet-Ruche contributed equally to this work.


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