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Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G.

ABSTRACT: The HIV-1-envelope (Env) trimer is covered by a glycan shield of ?90 N-linked oligosaccharides, which comprises roughly half its mass and is a key component of HIV evasion from humoral immunity. To understand how antibodies can overcome the barriers imposed by the glycan shield, we crystallized fully glycosylated Env trimers from clades A, B, and G, visualizing the shield at 3.4-3.7 Å resolution. These structures reveal the HIV-1-glycan shield to comprise a network of interlocking oligosaccharides, substantially ordered by glycan crowding, that encase the protein component of Env and enable HIV-1 to avoid most antibody-mediated neutralization. The revealed features delineate a taxonomy of N-linked glycan-glycan interactions. Crowded and dispersed glycans are differently ordered, conserved, processed, and recognized by antibody. The structures, along with glycan-array binding and molecular dynamics, reveal a diversity in oligosaccharide affinity and a requirement for accommodating glycans among known broadly neutralizing antibodies that target the glycan-shielded trimer.

SUBMITTER: Stewart-Jones GB

PROVIDER: S-EPMC5543418 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G.

Stewart-Jones Guillaume B E GB Soto Cinque C Lemmin Thomas T Chuang Gwo-Yu GY Druz Aliaksandr A Kong Rui R Thomas Paul V PV Wagh Kshitij K Zhou Tongqing T Behrens Anna-Janina AJ Bylund Tatsiana T Choi Chang W CW Davison Jack R JR Georgiev Ivelin S IS Joyce M Gordon MG Kwon Young Do YD Pancera Marie M Taft Justin J Yang Yongping Y Zhang Baoshan B Shivatare Sachin S SS Shivatare Vidya S VS Lee Chang-Chun D CC Wu Chung-Yi CY Bewley Carole A CA Burton Dennis R DR Koff Wayne C WC Connors Mark M Crispin Max M Baxa Ulrich U Korber Bette T BT Wong Chi-Huey CH Mascola John R JR Kwong Peter D PD

Cell 20160421 4

The HIV-1-envelope (Env) trimer is covered by a glycan shield of ∼90 N-linked oligosaccharides, which comprises roughly half its mass and is a key component of HIV evasion from humoral immunity. To understand how antibodies can overcome the barriers imposed by the glycan shield, we crystallized fully glycosylated Env trimers from clades A, B, and G, visualizing the shield at 3.4-3.7 Å resolution. These structures reveal the HIV-1-glycan shield to comprise a network of interlocking oligosaccharid ...[more]

PMID: 27114034

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Project description:BackgroundTen to 30% of HIV-1 infected subjects develop broadly neutralizing antibodies (bNAbs) during chronic infection. We hypothesized that immunizing rabbits with viral envelope glycoproteins (Envs) from these patients may induce bNAbs, when formulated as a trimeric protein and in the presence of an adjuvant.MethodsBased on in vitro neutralizing activity in serum, patients with bNAbs were selected for cloning of their HIV-1 Env. Seven stable soluble trimeric gp140 proteins were generated from sequences derived from four adults and two children infected with either clade A or B HIV-1. From one of the clade A Envs both the monomeric and trimeric Env were produced for comparison. Rabbits were immunized with soluble gp120 or trimeric gp140 proteins in combination with the adjuvant dimethyl dioctadecyl ammonium/trehalose dibehenate (CAF01). Env binding in rabbit immune serum was determined using ELISAs based on gp120-IIIB protein. Neutralizing activity of IgG purified from rabbit immune sera was measured with the pseudovirus-TZMbl assay and a PBMC-based neutralization assay for selected experiments.ResultsIt was initially established that gp140 trimers induce better antibody responses over gp120 monomers and that the adjuvant CAF01 was necessary for such strong responses. Gp140 trimers, based on HIV-1 variants from patients with bNAbs, were able to elicit both gp120IIIB specific IgG and NAbs to Tier 1 viruses of different subtypes. Potency of NAbs closely correlated with titers, and an gp120-binding IgG titer above a threshold of 100,000 was predictive of neutralization capability. Finally, peptide inhibition experiments showed that a large fraction of the neutralizing IgG was directed against the gp120 V3 region.ConclusionsOur results indicate that the strategy of reverse immunology based on selected Env sequences is promising when immunogens are delivered as stabilized trimers in CAF01 adjuvant and that the rabbit is a valuable model for HIV vaccine studies.

Dataset Information

Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G.

Publications

Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G.

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