title: HIV-1 envelope proteins and V1/V2 domain scaffolds with mannose-5 to improve the magnitude and quality of protective antibody responses to HIV-1.
abstract: Two lines of investigation have highlighted the importance of antibodies to the V1/V2 domain of gp120 in providing protection from HIV-1 infection. First, the recent RV144 HIV-1 vaccine trial documented a correlation between non-neutralizing antibodies to the V2 domain and protection. Second, multiple broadly neutralizing monoclonal antibodies to the V1/V2 domain (e.g. PG9) have been isolated from rare infected individuals, termed elite neutralizers. Interestingly, the binding of both types of antibodies appears to depend on the same cluster of amino acids (positions 167–171) adjacent to the junction of the B and C strands of the four-stranded V1/V2 domain β-sheet structure. However, the broadly neutralizing mAb, PG9, additionally depends on mannose-5 glycans at positions 156 and 160 for binding. Because the gp120 vaccine immunogens used in previous HIV-1 vaccine trials were enriched for complex sialic acid-containing glycans, and lacked the high mannose structures required for the binding of PG9-like mAbs, we wondered if these immunogens could be improved by limiting glycosylation to mannose-5 glycans. Here, we describe the PG9 binding activity of monomeric gp120s from multiple strains of HIV-1 produced with mannose-5 glycans. We also describe the properties of glycopeptide scaffolds from the V1/V2 domain also expressed with mannose-5 glycans. The V1/V2 scaffold from the A244 isolate was able to bind the PG9, CH01, and CH03 mAbs with high affinity provided that the proper glycans were present. We further show that immunization with A244 V1/V2 fragments alone, or in a prime/boost regimen with gp120, enhanced the antibody response to sequences in the V1/V2 domain associated with protection in the RV144 trial.
authors.forename: Javier F
authors.initials: JF
authors.lastname: Morales
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Morin
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.forename: Gwen P
authors.initials: GP
authors.lastname: Tatsuno
authors.forename: Sara M
authors.initials: SM
authors.lastname: O'Rourke
authors.forename: Richard
authors.initials: R
authors.lastname: Theolis
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Mesa
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Berman
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D006031:Glycosylation; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008358:Mannose / Q000235:genetics / Q000276:immunology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011817:Rabbits
chemical_list: D016915:AIDS Vaccines; D058846:Antibodies, Monoclonal, Murine-Derived; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1; D008358:Mannose