Envelope glycans of immunodeficiency virions are almost entirely oligomannose antigens

Abstract

The envelope spike of HIV is one of the most highly N-glycosylated structures found in nature. However, despite extensive research revealing essential functional roles in infection and immune evasion, the chemical structures of the glycans on the native viral envelope glycoprotein gp120-as opposed to recombinantly generated gp120 -have not been described. Here, we report on the identity of the N-linked glycans from primary isolates of HIV-1 (clades A, B, and C) and from the simian immunodeficiency virus. MS analysis reveals a remarkably simple and highly conserved virus-specific glycan profile almost entirely devoid of medial Golgi-mediated processing. In stark contrast to recombinant gp120, which shows extensive exposure to cellular glycosylation enzymes (>70% complex type glycans), the native envelope shows barely detectable processing beyond the biosynthetic intermediate Man 5 GlcNAc 2 (<2% complex type glycans). This oligomannose (Man 5-9 GlcNAc 2 ) profile is conserved across primary isolates and geographically divergent clades but is not reflected in the current generation of gp120 antigens used for vaccine trials. In the context of vaccine design, we also note that Manα1→2Man-terminating glycans (Man 6-9 GlcNAc 2 ) of the type recognized by the broadly neutralizing anti-HIV antibody 2G12 are 3-fold more abundant on the native envelope than on the recombinant monomer and are also found on isolates not neutralized by 2G12. The Manα1→2-Man residues of gp120 therefore provide a vaccine target that is physically larger and antigenically more conserved than the 2G12 epitope itself. This study revises and extends our understanding of the glycan shield of HIV with implications for AIDS vaccine design.HIV | 2G12 | gp120 | glycosylation | vaccine

Structural Insights into the Anti-HIV Activity of the Oscillatoria agardhii Agglutinin Homolog Lectin Family

“…Anti-HIV Activities of PFA and MBHA-The OAA anti-HIV activity is mediated by the specific recognition of ␣3,␣6-mannopentaose, the branched core unit of Man-8 and Man-9 (23, 38), major high mannose sugars on the HIV-1 envelope glycoprotein gp120 (39). Here, we show that both PFA and MBHA also interact with this glycan structure, suggesting possible similar activities for these lectins.…”

MALDI-MS/MS with Traveling Wave Ion Mobility for the Structural Analysis ofN-Linked Glycans

“…Thus, MALDI, followed by ion mobility and CID fragmentation can be used to examine the products of enzymatic glycan release without additional clean-up, allowing for rapid analysis, and can also be used to great advantage with samples containing very little glycan material, such as the analysis of HIV glycans from infectious virions [70,71].…”

Synthetic Carbohydrate Antigens for HIV Vaccine Design

“…O-glycosylation was rarely found for HIV-1 envelope, although a recent report suggests the existence of O-glycans on some gp120 [13]. HIV-1 glycosylation is tremendously heterogeneous [12,[14][15][16][17][18]. On top of the structural heterogeneity, one important feature of HIV-1 glycosylation is the unusually high numbers of high-mannose type glycans on gp120 [12].…”

“…On top of the structural heterogeneity, one important feature of HIV-1 glycosylation is the unusually high numbers of high-mannose type glycans on gp120 [12]. This tendency was even greater for the virionassociated gp120 from primary HIV-1 isolates as well as the simian immunodeficiency virus (SIV) [16,18]. Another important feature is the clustering of glycans on gp120.…”