Quaternary Epitope Specificities of Anti-HIV-1 Neutralizing Antibodies Generated in Rhesus Macaques Infected by the Simian/Human Immunodeficiency Virus SHIV_SF162P4

Abstract

Monoclonal antibodies (MAbs) that neutralize human immunodeficiency virus type 1 (HIV-1) have been isolated from HIV-1-infected individuals or animals immunized with recombinant HIV-1 envelope (Env) glycoprotein constructs. The epitopes of these neutralizing antibodies (NAbs) were shown to be located on either the variable or conserved regions of the HIV-1 Env and to be linear or conformational. However, one neutralizing MAb, 2909, which was isolated from an HIV-1-infected subject, recognizes a more complex, quaternary epitope that is present on the virion-associated functional trimeric Env spike of the SF162 HIV-1 isolate. Here, we discuss the isolation of 11 anti-HIV NAbs that were isolated from three rhesus macaques infected with the simian/human immunodeficiency virus SHIV SF162P4 and that also recognize quaternary epitopes. A detailed epitope mapping analysis of three of these rhesus antibodies revealed that their epitopes overlap that of the human MAb 2909. Despite this overall similarity in binding, however, differences in specific amino acid and glycosylation pattern requirements for MAb 2909 and the rhesus MAbs were identified. These results highlight similarities in the B-cell responses of humans and macaques to structurally complex neutralization epitopes on related viruses, HIV-1 and SHIV.

Intraprotomer masking of third variable loop (V3) epitopes by the first and second variable loops (V1V2) within the native HIV-1 envelope glycoprotein trimer

“…Our data suggesting cis masking are consistent with recent binding studies suggesting that the quaternary epitopes for mAbs PG9 and PG16 are composed of determinants on V2 and V3 within the same gp120 subunit (22). It would be interesting to apply our approach based on neutralization of complementing mixed trimers to these and other reported V2/V3-dependent quaternary epitopes (47,48).…”

The Thai Phase III HIV Type 1 Vaccine Trial (RV144) Regimen Induces Antibodies That Target Conserved Regions Within the V2 Loop of gp120

“…39 Broadly neutralizing antibodies that interact with quaternary neutralizing epitopes (QNE) of trimeric native Env spikes have been shown to interact with conserved aa embedded within the variable (V) loops of gp120 including the V2 loop. [40][41][42][43][44][45][46][47] Furthermore, antibodies found in individuals that exhibit potent cross-clade neutralizing activity have been shown to target conserved regions of the V1, V2, and V3 loops, providing evidence that V2 contributes to the formation of QNE that can induce potent cross-clade neutralizing antibodies. 25,43 The structure of scaffolded V1/V2 complexed with the broadly neutralizing monoclonal antibody PG9 has been resolved.…”

Potent and Broad Neutralization of HIV-1 Subtype C by Plasma Antibodies Targeting a Quaternary Epitope Including Residues in the V2 Loop

“…Similar neutralizing MAbs from rhesus macaques infected with simian/human immunodeficiency virus SF162P4 (2.2G, 2.3E, and 2.5B) target the same overall QNE, though each possesses distinct amino acid and glycan requirements (34). Although these antibodies are very potent, they are also extremely type specific, neutralizing only SF162.…”