Identification of an HIV-1 Clade A Envelope That Exhibits Broad Antigenicity and Neutralization Sensitivity and Elicits Antibodies Targeting Three Distinct Epitopes

Abstract

f ; Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA g 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.

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

“…PG16 and PGT141-145) appear much more dependent on quaternary interactions in the envelope trimer for binding and may, in the case of PG16, also depend on sialylated glycans at Asn-156 and sequences outside of the V1/V2 domain for binding (26). Several studies have also reported the binding of PG9 and PG9-like antibodies to monomeric gp120s and/or V1/V2 scaffolds from selected strains of HIV-1 (22,25,30,54,(63)(64)(65)82). In this regard, the ability to bind one PG9-like antibody does not predict the ability to bind other PG9-like antibodies.…”

HIV-1 neutralizing antibodies induced by native-like envelope trimers

“…The sequence of a week-6 clone is the basis of the BG505 SOSIP.664 protein construct, in which a T332N substitution was made to restore bNAb epitopes that require the N332 glycan (7–9, 24). The same change was made to create the BG505.T332N variant of the week-6 BG505 virus (9).…”

Structure-based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies

“…Antisera from cyclically permuted gp120 trimers show higher binding to the CD4 binding site focused outer domain immunogens than antisera from JRFL gp20 and JRFLgp120-L6-hCMP. gp120 binding titers (45,56,57) when a DNA prime-protein boost strategy was adopted.…”