Elicitation of broadly reactive antibodies against glycan-modulated neutralizing V3 epitopes of HIV-1 by immune complex vaccines.
HIV-1 envelope gp120 is the target for neutralizing antibodies (NAbs) against the virus. Various approaches have been explored to improve immunogenicity of broadly neutralizing epitopes on this antigen with limited success. We previously demonstrated that immunogenicity of gp120 and especially its V3 epitopes was enhanced when gp120 was co-administered as immune-complex vaccines with monoclonal antibodies (mAb) to the CD4-binding site (CD4bs). To define the mechanisms by which immune complexes influence V3 immunogenicity, we compared gp120 complexed with mAbs specific for the C2 region (1006-30), the V2 loop (2158), or the CD4bs (654), and found that the gp120/654 and gp120/2158 complexes elicited anti-V3 NAbs, but the gp120/654 complex was the most effective. gp120 complexed with 654 F(ab')2 was as potent, indicating that V3 immunogenicity is determined by the specificity of the mAb's Fab fragment used to form the complexes. Importantly, the gp120/654 complex not only induced anti-gp120 antibodies (Abs) to higher titers, but also of greater avidity. The Abs were cross-reactive with V3 peptides from most subtype B and some subtype C isolates. Neutralization was detected only against Tier-1 HIV-1 pseudoviruses, while Tier-2 viruses, including the homologous JRFL strain, were not neutralized. However, JRFL produced in the presence of a mannosidase inhibitor was sensitive to anti-V3 NAbs in the immune sera. These results demonstrate that the gp120/654 complex is a potent immunogen for eliciting cross-reactive functional NAbs against V3 epitopes, of which exposure is determined by the specific compositions of glycans shrouding the HIV-1 envelope glycoproteins.
VA New York Harbor Healthcare System, Manhattan Campus and New York University School of Medicine, Department of Pathology, New York, NY 10010, United States.
Rajnish
R
Kumar
Michael
M
Tuen
Jianping
J
Liu
Arthur
A
Nàdas
Ruimin
R
Pan
Xiangpeng
X
Kong
Catarina E
CE
Hioe
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000915:Antibody Affinity; D000936:Antigen-Antibody Complex / Q000008:administration & dosage / Q000276:immunology*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005260:Female; D015483:HIV Antibodies / Q000097:blood*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology*; D008807:Mice, Inbred BALB C; D011134:Polysaccharides / Q000276:immunology*
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D000936:Antigen-Antibody Complex; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D011134:Polysaccharides; C514793:gp120 protein, Human immunodeficiency virus 1
Abs; Antibody; CD4-binding site of HIV-1 gp120; CD4bs; DDA; HIV-1 envelope gp120; Immune complex; MPL; N-linked glycans; NAbs; NaSCN; Neutralization; V3 loop; Vaccine; antibodies; dimethyldioctadecylammonium bromide; mAbs; monoclonal antibodies; monophosphoryl lipid A; neutralizing antibodies; sodium thiocyanate