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Human immunodeficiency virus type 1 Envelope (HIV-1-Env) trimer consists of two types of viral envelope proteins, glycoprotein 41 and glycoprotein 120. These glycoproteins enable the encapulated HIV to attach to target cells and allow for membrane fusion to occur. As a result the target cell becomes infected. The glycoproteins are located on the surface of the virus, forming a spike. HIV-1-Env trimer is covered with a glycan shield, which works against the immune system by blocking antibodies. The glycan shield is composed of oligosaccharides (simple sugars) and its main function is to hide gp120 and gp41 of HIV-1 from antibody recognition. The glycan shield makes up half of the protein's mass.
From the major group (M group), three distinct clades (or taxonomic grouping) of the pre-fusion HIV-1-Env trimer in closed state were crystallized: A, B, and G. It was found that the glycan shield from each clade varies in glycan conformation/orientation and glycan-glycan interactions. However, the crowding and dispersing glycan remains conserved in the glycan shields of the A, B, and G clades. Through the binding of eleven different antibodies to the HIV-1-Env trimer, broadly neutralizing antibodies were found to have a high-affinity for glycan and therefore bind to it. Structural studies of these crystallized structures may allow for the design of a genetically modified HIV-1-Env trimer. Glycans could be removed from the shielding in order for neutralizing antibodies to enter the Env trimer. This could lead to the design of a vaccine against HIV.
II. HIV-1-Env Trimer Structure of Clades A, B, and G
HIV-1-Env trimer consist of two subunits, glycoprotein 41 and glycoprotein 120 (shown at left is the clade G model). The rest of the structure are the antibodies bound to the glycan shield. The antibodies crystallized in the three distinct clades show strain-dependent variation. For example, glycan N137, which recognizes antibody PGT122, is ordered in clade A, but disorded in clade B and displaced by a V1 extension (variable loop of gp120) in clade G. Although the glycan shield varies among the three distinct clades, the N-linked glycans all have the same function, which is to encase the pre-fusion HIV-1-Env trimer and protect the virus from immune recognition.
Fully glycosylated HIV-1-Env trimer from clade A strain BG505 was crystallized and data was collected with a resolution of 3.7 angstrom (Å). Gp41 and gp120 are shielded by N-linked glycans.
Antibodies 35O22 and PGT122 are bound to glycans shielding gp120.
Clade B:Fully glycosylated HIV-1-Env trimer from clade B strain JR-FL was crystallized and data was collected with a resolution of 3.7 Å. Gp41 and gp120 are shielded by N-linked glycans.
Antibodies 35O22, PGT122, and VRC01 are bound to glycans shielding gp120. VRC01 interacts with glycan N276 of the closed Env trimer. The glycan shield of clade B differ from clade A through glycan organization, such as differences in the positions of glycan sequons and in the amino acid residues placed near N-linked glycans.
Fully glycosylated HIV-1-Env trimer from clade G X1193.c1 was crystallized and data was collected with a resolution of 3.4 Å. There are 31 N-linked glycans shielding the gp41 and gp120 subunits. Electron density was observed for 29 of the 31 N-linked glycans.
Antibodies 35O22, PGT122, and VRC01 are bound to glycans shielding gp120. Three glycans demonstrated broad interactions with antibodies (N88 to 35O22, N276 to VRC01, and N332 to PGT122).
III. Glycan-Glycan Interactions
The glycan shield evolves along with the mutating RNA virus. The glycans are N-linked, a glycan (or oligosaccharide) attached to a nitrogen in the side chain of asparagine (Asn). Each N-linked glycan is encoded by a tripeptide (Asn-X-Ser and Asn-X-Thr) known as the N-glycan sequon. Oligosaccharyltransferase with the Glc3Man9(GlcNAc)2 sequence recognizes and attaches to the asparagine of the N-glycan sequon. There are 93 of these N-linked glycans covering the surface of the HIV-1-Env spike.
There are three categories of glycans based on the distances of N-glycan sequons:
Category I: 4-7 Å inter-glycan sequon distances
- Stem-stem forking is when glycan sequons are closely juxtaposed within 4 Å. The glycans (N413 and N332) make interaction between the GlcNAc2 stems.
- Stem-stem alignment is when glycan sequons are further apart than 4 Å as shown in stem-stem forking. The distance between the glycans (N363 and N386) is 6 Å and they tend to align parallel to one another.
Category II: 9-18 Å inter-glycan sequon distances
- Branch-branch engagement is where the glycans make interactions between the oligomannose branches rather than between the GlcNAc2 stems. The glycan sequons (N234 and N276) are 12 Å apart.
- Stem-branched association is where the glycans make interactions between the oligomannose branch and the GlcNAc2 stem. The glycan sequons (N442 and N413) are 16 Å apart.
- The quaternary axial cage produces a "forest effect", which is when the spacing of sequons allow for strong interaction with one another, leading to the formation of a oligosaccharide cover over the protein surface. These glycan-glycan interactions inhibit steric hindrance or access of antibodies to the protein surface. Glycans N188 and N160 (on the far left) are 17 Å apart while the three N160 glycans are 20 Å apart from one another.
- Triple entanglements are three glycan sequons clustered together and interlocked with one another. Glycans N362 and N386 are 16 Å apart while glycans N386 and N187 are 22 Å apart. The distance between glycans N362 and N187 is 31 Å.
- Long-range branch-to-branch creates a "mesh effect" by two or more oligosaccharides locally interacting. The glycan sequons (N293 and N241) are 30 Å apart and this interaction inhibits steric access of antibodies to the protein surface.
Category III: Greater than 20 Å inter-glycan sequon distances
- A single glycan is isolated and shields a local patch, which is known as an "umbrella effect." This glycan-glycan interaction also inhibits steric access of antibodies to the protein surface.
Stewart-Jones, G. B.E., Soto, C., Lemmin, T., Chuang, G., Druz, A., Kong, R., Thomas, P. V., Wagh, K., Zhou, T., Behrens, A., Bylund, T. Choi, C. W., Davison, J. R., Georgiev, I. S., Joyce, M. G., Kwon, Y., Pancera, M., Taft, J., Yang, Y., Zhang, B., Shivatare, S. S., Shivatare, V. S., Lee, C. D., Wu, C., Bewley, C. A., Burton, D. R., Koff, W. C., Connors, M., Crispin, M., Baxa, U., Korber, B. T., Wong, C., Mascola, J. R., and Kwong, P. D. (2016). Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G. Cell Press 165: 813-826.