Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1

Abstract

We have isolated and characterized human monoclonal antibody 2G12 to the gp120 surface glycoprotein of human immunodeficiency virus type 1 (HIV-1). This antibody potently and broadly neutralizes primary and T-cell line-adapted clade B strains of HIV-1 in a peripheral blood mononuclear cell-based assay and inhibits syncytium formation in the AA-2 cell line. Furthermore, 2G12 possesses neutralizing activity against strains from clade A but not from clade E. Complement-and antibody-dependent cellular cytotoxicity-activating functions of 2G12 were also defined. The gp120 epitope recognized by 2G12 was found to be distinctive; binding of 2G12 to LAI recombinant gp120 was abolished by amino acid substitutions removing N-linked carbohydrates in the C2, C3, V4, and C4 regions of gp120. This gp120 mutant recognition pattern has not previously been observed, indicating that the 2G12 epitope is unusual. Consistent with this, antibodies able to block 2G12 binding to recombinant gp120 were not detected in significant quantities in 16 HIV-positive human serum samples.

Characterization of a monoclonal antibody to a novel glycan-dependent epitope in the V1/V2 domain of the HIV-1 envelope protein, gp120

“…At this early stage of investigation, all antibodies to GDEs of the HIV-1 envelope protein are informative; however, antibodies to the V1/V2 domain of gp120 are of particular interest. First, the V1/V2 domain contains the GDEs recognized by several bN-mAbs (e.g., PG9, PG16, CH01-4, PGT145) (Walker et al, 2009(Walker et al, , 2011Pejchal et al, 2011;Sanders et al, 2002;Trkola et al, 1996;Mouquet et al, 2012;Bonsignori et al, 2011). Second, nonneutralizing antibodies to the V1/V2 domain represent the only antibody response found to correlate with protection in the RV144 HIV vaccine trial, which included immunization with the ALVAC-HIV canarypox vector vaccine (vCP1521) and the AIDSVAX B/E recombinant gp120 subunit vaccine (Berman, 1998;Berman et al, 1999;Rerks-Ngarm et al, 2009;Haynes et al, 2012).…”

HIV envelope: challenges and opportunities for development of entry inhibitors

“…Second, many of the conserved envelope regions might not be accessible due to high levels of glycosylation in the variable loops and relatively high mobility, which is sometimes referred to as the 'glycan shield' [6,46,47]. Counter intuitively, the monoclonal antibodies 2G12, PG9 and PG16, which neutralize HIV-1 from multiple clades, bind to glycosyl moieties or V2 and V3 of gp120 [48,49]. Nonetheless, the sequence variability, glycosylation and mobility make the envelope a moving target, which complicates the search for molecules that bind with high specificity.…”

“…Entry inhibitors have been discovered by a number of different strategies: (i) monoclonal antibodies; (ii) phage display; (iii) small molecule screening; (iv) structure-based drug design. Monoclonal antibodies that bind specifically to the HIV envelope (and block entry) can be found in patients exposed to HIV [48]. Phage display is performed by exposing a library of phage expressing short peptide regions (there are similar techniques that employ bacteria or yeast libraries) to the HIV envelope or CD4 and CR [89].…”

Plant made anti-HIV microbicides—A field of opportunity

“…It has been reported that 2G12 neutralises A and B clade HIV-1 virus entry by recognition of a Manα1→2Man rich epitope on the exterior face of the gp120 protein (Binley et al, 2004;Scanlan et al, 2002). Monoclonal antibody (MAb) 2G12 can activate the complement system and display antibody dependent cellular cytotoxicity (ADCC) against virus infected cells (Trkola et al, 1996). Passive infusion of 2G12 combined with other neutralising antibodies including 2F5, protected macaques from a vaginal and intravenous challenge with SHIV (Baba et al, 2000;Mascola et al, 2000).…”