High-Mannose Glycan-Dependent Epitopes Are Frequently Targeted in Broad Neutralizing Antibody Responses during Human Immunodeficiency Virus Type 1 Infection

Abstract

Broad and potent neutralizing antibody (BNAb) responses are rare in people infected by human immunodeficiency virus type 1 (HIV-1). Clearly defining the nature of BNAb epitopes on HIV-1 envelope glycoproteins (Envs) targeted in vivo is critical for future directions of anti-HIV-1 vaccine development. Conventional techniques are successful in defining neutralizing epitopes in a small number of individual subjects but fail in studying large groups of subjects. Two independent methods were employed to investigate the nature of NAb epitopes targeted in 9 subjects, identified by the NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI) 001 and 008 clinical teams, known to make a strong BNAb response. Neutralizing activity from 8/9 subjects was enhanced by enriching high-mannose N-linked glycan (HM-glycan) of HIV-1 glycoproteins on neutralization target viruses and was sensitive to specific glycan deletion mutations of HIV-1 glycoproteins, indicating that HM-glycan-dependent epitopes are targeted by BNAb responses in these subjects. This discovery adds to accumulating evidence supporting the hypothesis that glycans are important targets on HIV-1 glycoproteins for BNAb responses in vivo, providing an important lead for future directions in developing NAb-based anti-HIV-1 vaccines.

Enhanced Fusion and Virion Incorporation for HIV-1 Subtype C Envelope Glycoproteins with Compact V1/V2 Domains

“…Our findings have important implications for vaccine development, as V1/V2 domains are often targeted by neutralizing antibodies (56). In the RV144 Thai vaccine trial, the levels of antibodies directed against V1/V2 inversely correlated with infection risk (57,58).…”

Broadly Neutralizing Antibodies Developed by an HIV-Positive Elite Neutralizer Exact a Replication Fitness Cost on the Contemporaneous Virus

“…Later during the course of infection, approximately 15% of HIV-1-infected subjects develop neutralizing antibody responses against diverse heterologous HIV-1 viruses, and approximately 1% of HIV-positive (HIV ϩ ) subjects develop exquisitely potent and broad neutralizing antibody responses (4,8,13,19,21,23,32). In several wellcharacterized cases of such "elite neutralizers," the cross-neutralizing activities of sera were determined to be due to NAbs that target a small number of structurally conserved regions of env (4,6,13,17,19,21,32), including the CD4-binding site (CD4-BS) (1,7,35,44,46), and conserved elements of the variable loops V2 and V3, with the later specificities being glycan dependent (27,39).…”

Synthetic Carbohydrate Antigens for HIV Vaccine Design

“…In a relevant design, Davis and co-workers ligated a C-6 methylated Man4 to Qβ, providing a novel multivalent nonself sugar mimic of the HIV glycan shield (Figure 2f) [56•]. For the synthesis, surface-exposed amine groups on Qβ was functionalized with alkyne groups and then reacted with oligomannose-azides via an efficient CuAAC click reaction to afford the glycoconjugates carrying Man 4 , Man 8 , and/or Man 9 ( Figure 3). Three Qβ variants (Qβ, QβK16M, and Qβ-HPG) were used as scaffolds to investigate the effects of varied number and geometry of oligomannose attachments.…”

“…The initial identification of 2G12, a carbohydrate-specific broadly neutralizing antibody, suggests that the defensive carbohydrate shield of HIV is vulnerable for immune recognition. This notion was greatly reinforced by the recent discovery of more than a dozen of new glycan-dependent bnAbs, including PG9, PG16, PGT121-123, PGT125-128, and PGT135, which neutralize HIV-1 primary isolates with remarkable breadth and potency [6][7][8]. These findings has stimulated great interests in further characterization and reconstitution of the fine neutralizing epitopes, which are essential first steps in the design of an effective immunogen [5••,9].…”