Antibodies elicited by yeast glycoproteins recognize HIV-1 virions and potently neutralize virions with high mannose N-glycans.
The glycan shield on the human immunodeficiency virus 1 (HIV-1) envelope (Env) glycoprotein has drawn attention as a target for HIV-1 vaccine design given that an increasing number of potent and broadly neutralizing antibodies (bNAbs) recognize epitopes entirely or partially comprised of high mannose type N-linked glycans. In an attempt to generate immunogens that target the glycan shield of HIV-1, we previously engineered a triple mutant (TM) strain of Saccharomyces cerevisiae that results in exclusive presentation of high mannose type N-glycans, and identified five TM yeast glycoproteins that support strong binding of 2G12, a bNAb that targets a cluster of high mannose glycans on the gp120 subunit of Env. Here, we further analyzed the antigenicity and immunogenicity of these proteins in inducing anti-HIV responses. Our study demonstrated that the 2G12-reactive TM yeast glycoproteins efficiently bound to recently identified bNAbs including PGT125-130 and PGT135 that recognize high mannose glycan-dependent epitopes. Immunization of rabbits with a single TM yeast glycoprotein (Gp38 or Pst1), when conjugated to a promiscuous T-cell epitope peptide and coadministered with a Toll-like receptor 2 agonist, induced glycan-specific HIV-1 Env cross-reactive antibodies. The immune sera bound to both synthetic mannose oligosaccharides and gp120 proteins from a broad range of HIV-1 strains. The purified antibodies recognized and captured virions that contain both complex- and high mannose-type of N-glycans, and potently neutralized virions from different HIV-1 clades but only when the virions were enforced to retain high mannose N-glycans. This study provides insights into the elicitation of anti-carbohydrate, HIV-1 Env-cross reactive antibodies with a heterologous glycoprotein and may have applications in the design and administration of immunogens that target the viral glycan shield for development of an effective HIV-1 vaccine.
ProSci Incorporated, Poway, CA 92064, USA.
Hong
H
Zhang
ProSci Incorporated, Poway, CA 92064, USA.
Hu
H
Fu
ProSci Incorporated, Poway, CA 92064, USA.
Robert J
RJ
Luallen
ProSci Incorporated, Poway, CA 92064, USA.
Bingfen
B
Liu
Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Fang-Hua
FH
Lee
Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Robert W
RW
Doms
ProSci Incorporated, Poway, CA 92064, USA. Electronic address: ygeng@prosci-inc.com.
Yu
Y
Geng
D000818:Animals; D000908:Antibodies, Fungal / Q000276:immunology*; D000910:Antibodies, Heterophile / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D009500:Neutralization Tests; D011134:Polysaccharides / Q000276:immunology*; D011817:Rabbits; D012441:Saccharomyces cerevisiae / Q000276:immunology*
D000908:Antibodies, Fungal; D000910:Antibodies, Heterophile; D057134:Antibodies, Neutralizing; D011134:Polysaccharides
AIDS; Adjuvant; Carbohydrate; Glycoproteins; HIV-1; Neutralizing antibody; Vaccine