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

被引：57

作者：

Forsell, Mattias N. E. ^{[1
,2
,3
]}

Dey, Barna ^{[1
]}

Moerner, Andreas ^{[3
]}

Svehla, Krisha ^{[1
]}

O'dell, Sijy ^{[1
]}

Hoegerkorp, Carl-Magnus ^{[1
]}

Voss, Gerald ^{[4
]}

Thorstensson, Rigmor ^{[3
]}

Shaw, George M. ^{[5
]}

Mascola, John R. ^{[1
]}

Hedestam, Gunilla B. Karlsson ^{[2
,3
]}

Wyatt, Richard T. ^{[1
]}

机构：

[1] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA

[2] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden

[3] Swedish Inst Infect Dis Control, Solna, Sweden

[4] GlaxoSmithKline Biol, Rixensart, Belgium

[5] Univ Alabama, Birmingham, AL USA

来源：

PLOS PATHOGENS | 2008年 / 4卷 / 10期

关键词：

D O I：

10.1371/journal.ppat.1000171

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

The surface HIV-1 exterior envelope glycoprotein, gp120, binds to CD4 on the target cell surface to induce the coreceptor 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 naive 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.

引用

页数：12