Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120

  title={Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120},
  author={Leopold Kong and Jeong Hyun Lee and Katie J. Doores and Charles D. Murin and Jean-Philippe Julien and Ryan McBride and Yan Liu and Andre J. Marozsan and Albert Cupo and Per Johan Klasse and Simon Hoffenberg and Michael P. Caulfield and C. Richter King and Yuanzi Hua and Khoa Le and Reza Khayat and Marc C. Deller and Thomas Clayton and Henry Tien and Ten Feizi and Rogier W. Sanders and James C. Paulson and John P. Moore and Robyn L. Stanfield and Dennis R. Burton and Andrew B. Ward and Ian A. Wilson},
  journal={Nature structural \& molecular biology},
  pages={796 - 803}
A substantial proportion of the broadly neutralizing antibodies (bnAbs) identified in certain HIV-infected donors recognize glycan-dependent epitopes on HIV-1 gp120. Here we elucidate how the bnAb PGT 135 binds its Asn332 glycan–dependent epitope from its 3.1-Å crystal structure with gp120, CD4 and Fab 17b. PGT 135 interacts with glycans at Asn332, Asn392 and Asn386, using long CDR loops H1 and H3 to penetrate the glycan shield and access the gp120 protein surface. EM reveals that PGT 135 can… 

The HIV glycan shield as a target for broadly neutralizing antibodies

The changing perception of the HIV glycan shield is discussed, and the protein‐directed and cell‐directed factors controlling HIV Env glycosylation that impact on HIV bnAb recognition and HIV vaccine design strategies are summarized.

Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site

A glycan shield of high-mannose and complex-type N-glycans is presented, which was used to define complete epitopes of two bNAbs and has implications for immunization strategies targeting VRC01-like bNABS.

Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike

Using biochemical, biophysical and computational methods, the previously unknown trimer epitopes of two related antibodies, 3BC315 and 3BC176 are mapped and it is suggested that the dynamic structure of the Env trimer influences exposure of bnAb epitopes.

Networks of HIV-1 Envelope Glycans Maintain Antibody Epitopes in the Face of Glycan Additions and Deletions

Glycan networks underpin the conservation of bnAb epitopes and are an important parameter in immunogen design and it is shown that the PG9 and PG16 glycan-based epitopes at the trimer apex are dependent on the presence of the highly conserved surrounding glycans.

Probability of N332 glycan occupancy on HIV-1 gp120 modulates sensitivity to broadly neutralizing antibodies

Observations suggest that modulation of N332 glycan occupancy by the second amino acid position of the canonical glycosylation motif Asn-X-Ser plays a previously unappreciated role in viral escape from immune responses, and should be considered in Env-based vaccine design.

Glycan clustering stabilizes the mannose patch of HIV-1 and preserves vulnerability to broadly neutralizing antibodies

The contribution of individual glycosylation sites to formation of this so-called intrinsic mannose patch is investigated and it is shown that structural changes are largely tolerated by a panel of glycan-dependent bnAbs targeting these regions, indicating a degree of plasticity in their recognition.



A Potent and Broad Neutralizing Antibody Recognizes and Penetrates the HIV Glycan Shield

The data suggest that the high neutralization potency of PGT 127 and 128 immunoglobulin Gs may be mediated by cross-linking Env trimers on the viral surface.

Structural Basis of Immune Evasion at the Site of CD4 Attachment on HIV-1 gp120

Co-crystal structures for two poorly neutralizing, CD4–binding site (CD4BS) antibodies, F105 and b13, in complexes with gp120 are determined, finding these conformations to be poorly compatible with the viral spike.

Structural definition of a conserved neutralization epitope on HIV-1 gp120

A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.

Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9

Structural and biophysical findings should facilitate the design of HIV-1 immunogens that possess all elements of the quaternary PG9 epitope required to induce broadly neutralizing antibodies against this region.

Role of Complex Carbohydrates in Human Immunodeficiency Virus Type 1 Infection and Resistance to Antibody Neutralization

The data show that the antennae of complex N-glycans serve to protect the V3 loop and CD4 binding site, while N- glycan stems regulate native trimer conformation, such that their removal can lead to global changes in neutralization sensitivity and, in extreme cases, an inability to complete the conformational rearrangements necessary for infection.

Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape

It is shown, in two HIV-1–infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus, which highlights the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes.

Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9

The structure of V1/V2 in complex with PG9 is reported, identifying a paradigm of antibody recognition for highly glycosylated antigens, which—with PG9—involves a site of vulnerability comprising just two glycans and a strand.

Polysaccharide mimicry of the epitope of the broadly neutralizing anti-HIV antibody, 2G12, induces enhanced antibody responses to self oligomannose glycans.

It is reported that modulation of yeast polysaccharide biosynthesis directly controls the molecular specificity of cross-reactive antibodies to self oligomannose glycans, confirming the Manalpha1-->2Man motif as the primary carbohydrate neutralization determinant of HIV-1 and showing that the genetic modulation of microbialpolysaccharides is a route towards immunogens capable of eliciting antibody responses to the glycans of HIV -1.

Molecular architecture of native HIV-1 gp120 trimers

It is demonstrated that CD4 binding results in a major reorganization of the Env trimer, causing an outward rotation and displacement of each gp120 monomer, leading to closer contact between the viral and target cell membranes.

Heterologous Epitope-Scaffold Prime∶Boosting Immuno-Focuses B Cell Responses to the HIV-1 gp41 2F5 Neutralization Determinant

It is found that the heterologous ES prime∶boosting immunization regimen elicits cross-reactive humoral responses to the structurally constrained 2F5 epitope target, and that incorporating a promiscuous T cell helper epitope in the immunogens resulted in higher antibody titers against the 2F 5 graft, but did not result in virus neutralization.