Identification of a New Quaternary Neutralizing Epitope on Human Immunodeficiency Virus Type 1 Virus Particles

Abstract

The selection of human monoclonal antibodies (MAbs) specific for human immunodeficiency virus (HIV) type 1 by binding assays may fail to identify Abs to quaternary epitopes on the intact virions. The HIV neutralization assay was used for the selection of human MAb 2909, which potently neutralizes SF162 and recognizes an epitope on the virus surface but not on soluble proteins. Three regions of gp120, the V2 and V3 loops and the CD4 binding domain, contribute to the epitope recognized by MAb 2909. The existence of such a unique MAb, which defines a complex epitope formed by a quaternary structure, suggests that there may be other new neutralizing HIV epitopes to target with vaccines.

Type-Specific Epitopes Targeted by Monoclonal Antibodies with Exceptionally Potent Neutralizing Activities for Selected Strains of Human Immunodeficiency Virus Type 1 Map to a Common Region of the V2 Domain of gp120 and Differ Only at Single Positions from the Clade B Consensus Sequence

“…However, several anti-V2 MAbs possess unusually potent type-specific neutralizing activities. These include C108g, directed against a complex epitope localized in the V2 domain (36,40), and 2909, the first anti-HIV MAb that reacts specifically with a quaternary epitope restricted to native Env oligomers present on the surface of intact virion particles (14). The epitopes recognized by these MAbs have not been well characterized, and thus, the potential utility of these and related epitopes as vaccine targets is unclear.…”

“…2909 was isolated from an asymptomatic HIV-infected patient by screening directly for neutralizing activity against SF162 pseudotypes (14). This MAb possesses remarkably potent neutralizing activity for SF162, with a 50% inhibitory concentration (IC 50 ) value reported to be significantly lower than that of any previously described MAb, including the broadly cross-reactive MAbs 2F5, b12, and 2G12.…”

HIV-1 Glycoprotein Immunogenicity

“…Trimerization can result in changes in quaternary structure within individual subunits or through reorientation of the subunits against each other, so regions contributing to the quaternary epitope can be inter-molecular (trans) or intra-molecular (cis). Recently, a human mAb (mAb 2909) (figure 14) has been described to bind to a quaternary structure only on virion but not to soluble monomeric gp120 (Changela et al, 2011;Gorny et al, 2005). It has been discovered by immortalization of PBMC from HIV 1 patients asymptomatic and drug-naïve (Gorny et al, 1991).…”

“…It has been discovered by immortalization of PBMC from HIV 1 patients asymptomatic and drug-naïve (Gorny et al, 1991). It demonstrates a high neutralizing activity for primary isolate such as SF162 (picomolar concentrations) and specificity for a complex epitope consisting of V2, V3, and the CD4 binding site that is present exclusively on the surfaces of intact virions but not on soluble viral proteins (Gorny et al, 2005). The neutralizing activity of MAb 2909 against pseudovirus SF162 is 750-to 100,000-fold more potent than those of other well-characterized.…”

“…An Ab that reacts with a true quaternary epitope will not interact with the individual monomeric subunits. Monoclonal antibodies mAb2909 and PG16 (figure 14), react with the trimeric form of gp120 on the surface of HIV-1 virions or env-transfected cells but not with monomeric gp120 (Gorny et al, 2005;Walker et al, 2009). However, some Abs that react with quaternary epitopes binds preferentialy the trimers rather than monomeric subunits.…”