B cell recognition of the conserved HIV-1 co-receptor binding site is altered by endogenous primate CD4.
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.
Forsell
Mattias N E
MN
Vaccine Research Center, NIH, Bethesda, MD, USA.
Dey
Barna
B
Mörner
Andreas
A
Svehla
Krisha
K
O'dell
Sijy
S
Högerkorp
Carl-Magnus
CM
Voss
Gerald
G
Thorstensson
Rigmor
R
Shaw
George M
GM
Mascola
John R
JR
Karlsson Hedestam
Gunilla B
GB
Wyatt
Richard T
RT
D000818:Animals; D000914:Antibodies, Viral / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008252:Macaca fascicularis; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology; D011817:Rabbits; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D013045:Species Specificity; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
D000914:Antibodies, Viral; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D046912:Multiprotein Complexes; D011947:Receptors, Antigen, B-Cell; D054299:env Gene Products, Human Immunodeficiency Virus; C514793:gp120 protein, Human immunodeficiency virus 1