title: Identification of an HIV-1 clade A envelope that exhibits broad antigenicity and neutralization sensitivity and elicits antibodies targeting three distinct epitopes.
abstract: Broadly neutralizing antibodies (bNAbs) PG9 and PG16 were isolated from an International AIDS Vaccine Initiative (IAVI) Protocol G subject infected with human immunodeficiency virus type 1 (HIV-1) clade A. Both antibodies are highly potent and neutralize greater than 70% of viruses tested. We sought to begin immunogen design based on viral sequences from this patient; however, pseudoviruses prepared with 19 envelope sequences from this subject were resistant to neutralization by PG9 and PG16. Therefore, we used a bioinformatics approach to identify closely related viruses that were potentially sensitive to PG9 and PG16. A most-recent common ancestor (MRCA) sequence for the viral envelope (Env) was determined and aligned with 99 subtype A gp160 sequences from the Los Alamos HIV database. Virus BG505.W6M.ENV.C2 (BG505) was found to have the highest degree of homology (73%) to the MRCA sequence. Pseudoviruses prepared with this Env were sensitive to neutralization with a broad panel of bNAbs, including PG9 and PG16. When expressed by 293T cells as soluble gp120, the BG505 monomer bound well to both PG9 and PG16. We further showed that a point mutation (L111A) enabled more efficient production of a stable gp120 monomer that preserves the major neutralization epitopes. Finally, we showed that an adjuvanted formulation of this gp120 protein elicited neutralizing antibodies in rabbits (following a gp120 DNA vaccine prime) and that the antisera competed with bNAbs from 3 classes of nonoverlapping epitopes. Thus, the BG505 Env protein warrants further investigation as an HIV vaccine candidate, as a stand-alone protein, or as a component of a vaccine vector.
authors.affiliation: Vaccine Design and Development Lab, International AIDS Vaccine Initiative, Brooklyn, New York, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Hoffenberg
authors.forename: Rebecca
authors.initials: R
authors.lastname: Powell
authors.forename: Alexei
authors.initials: A
authors.lastname: Carpov
authors.forename: Denise
authors.initials: D
authors.lastname: Wagner
authors.forename: Aaron
authors.initials: A
authors.lastname: Wilson
authors.forename: Sergei
authors.initials: S
authors.lastname: Kosakovsky Pond
authors.forename: Ross
authors.initials: R
authors.lastname: Lindsay
authors.forename: Heather
authors.initials: H
authors.lastname: Arendt
authors.forename: Joanne
authors.initials: J
authors.lastname: Destefano
authors.forename: Sanjay
authors.initials: S
authors.lastname: Phogat
authors.forename: Pascal
authors.initials: P
authors.lastname: Poignard
authors.forename: Steven P
authors.initials: SP
authors.lastname: Fling
authors.forename: Melissa
authors.initials: M
authors.lastname: Simek
authors.forename: Celia
authors.initials: C
authors.lastname: Labranche
authors.forename: David
authors.initials: D
authors.lastname: Montefiori
authors.forename: Terri
authors.initials: T
authors.lastname: Wrin
authors.forename: Pham
authors.initials: P
authors.lastname: Phung
authors.forename: Dennis
authors.initials: D
authors.lastname: Burton
authors.forename: Wayne
authors.initials: W
authors.lastname: Koff
authors.forename: C Richter
authors.initials: CR
authors.lastname: King
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Parks
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Caulfield
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D019295:Computational Biology; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005838:Genotype; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120