B Cell Recognition of the Conserved HIV-1 Co-Receptor Binding Site Is Altered by Endogenous Primate CD4

PLoS Pathogens

Barna Dey¹  George M. Shaw²  Sijy O'dell³  Andreas Mörner³  John R. Mascola³  Gunilla B. Karlsson Hedestam⁴  Rigmor Thorstensson⁵  Krisha Svehla⁵  Gerald Voss⁵  Mattias N. E. Forsell⁵  Richard T. Wyatt⁵  Carl-Magnus Högerkorp⁵ 

[1] Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden;GlaxoSmithKline Biologicals, Rixensart, Belgium;Swedish Institute for Infectious Disease Control, Solna, Sweden;University of Alabama in Birmingham, Birmingham, Alabama, United States of America;Vaccine Research Center, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: Antibodies;    Enzyme-linked immunoassays;    Coreceptors;    HIV-1;    Primates;    CD coreceptors;    Monkeys;    Cell binding;   

DOI  :  10.1371/journal.ppat.1000171

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The surface HIV-1 exterior envelope glycoprotein, gp120, binds to CD4 on the target cell surface to induce the co-receptor binding site on gp120 as the initial step in the entry process. The binding site is comprised of a highly conserved region on the gp120 core, as well as elements of the third variable region (V3). Antibodies against the co-receptor binding site are abundantly elicited during natural infection of humans, but the mechanism of elicitation has remained undefined. In this study, we investigate the requirements for elicitation of co-receptor binding site antibodies by inoculating rabbits, monkeys and human-CD4 transgenic (huCD4) rabbits with envelope glycoprotein (Env) trimers possessing high affinity for primate CD4. A cross-species comparison of the antibody responses showed that similar HIV-1 neutralization breadth was elicited by Env trimers in monkeys relative to wild-type (WT) rabbits. In contrast, antibodies against the co-receptor site on gp120 were elicited only in monkeys and huCD4 rabbits, but not in the WT rabbits. This was supported by the detection of high-titer co-receptor antibodies in all sera from a set derived from human volunteers inoculated with recombinant gp120. These findings strongly suggest that complexes between Env and (high-affinity) primate CD4 formed in vivo are responsible for the elicitation of the co-receptor-site-directed antibodies. They also imply that the naïve B cell receptor repertoire does not recognize the gp120 co-receptor site in the absence of CD4 and illustrate that conformational stabilization, imparted by primary receptor interaction, can alter the immunogenicity of a type 1 viral membrane protein.

【 授权许可】

CC BY