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Review
. 1997 Sep 16;94(19):10018-23.
doi: 10.1073/pnas.94.19.10018.

A vaccine for HIV type 1: the antibody perspective

D R Burton  1
Affiliations
Review

A vaccine for HIV type 1: the antibody perspective

D R Burton. Proc Natl Acad Sci U S A. .

Abstract

Antibodies that bind well to the envelope spikes of immunodeficiency viruses such as HIV type 1 (HIV-1) and simian immunodeficiency virus (SIV) can offer protection or benefit if present at appropriate concentrations before viral exposure. The challenge in antibody-based HIV-1 vaccine design is to elicit such antibodies to the viruses involved in transmission in humans (primary viruses). At least two major obstacles exist. The first is that very little of the envelope spike surface of primary viruses appears accessible for antibody binding (low antigenicity), probably because of oligomerization of the constituent proteins and a high degree of glycosylation of one of the proteins. The second is that the mature oligomer constituting the spikes appears to stimulate only weak antibody responses (low immunogenicity). Viral variation is another possible obstacle that appears to present fewer problems than anticipated. Vaccine design should focus on presentation of an intact mature oligomer, increasing the immunogenicity of the oligomer and learning from the antibodies available that potently neutralize primary viruses.

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Figures

Figure 1
Figure 1
Schematic models of the exposed epitopes on isolated gp41, gp120, and the mature oligomer on the virion surface. The schematic model for gp41 structure is adapted from Weissenhorn et al. (4). A similar structure has been presented by Chan et al. (3). The crystal structures were solved for helical peptides lacking the interhelical region and the fusion peptide. These are included in this schematic representation. The structure corresponds to the “sprung” form of gp41 (see text). The fusion peptide at the N terminus of the protein is linked to an α-helix, which forms a coiled coil in the trimer (only a monomer unit is shown). A disulfide-bridged loop containing the immunodominant epitope links to a C-terminal α-helix, which packs against the core structure. A flexible region links the C-terminal helix to the transmembrane segment. Cluster I-III antibodies recognize three epitope regions as shown. The antibody 2F5 recognizes a region of gp41 close to the transmembrane domain. Further epitopes recognized by single mAbs have been defined. The schematic model for gp120 structure is adapted from Sodroski et al. (28), Poignard et al. (76), and Burton and Montefiori (15). The molecule is heavily glycosylated as represented by the Y-shapes. Antibody mapping indicates that C1, C5, V1/V2, and V3 regions and the CD4 binding site are at least partially accessible on monomeric gp120. C1 and C5 are on the “back side,” nonneutralizing face of this model. The b12 epitope overlaps the CD4 binding site but is also sensitive to V2 loop conformation. The 2G12 epitope appears to involve residues (including possibly carbohydrate structures) from V4 and the base of the V3 loop. Most of the epitopes accessible on isolated gp41 and gp120 molecules are also accessible on unprocessed forms of gp160. For the mature oligomer on the surface of TCLA viruses, many epitopes exposed on the isolated gp41 and gp120 molecules now are occluded by virtue of gp41-gp41 or gp41-gp120 interactions or proximity of monomeric units to one another or the virion surface. In particular on gp41, only the 2F5 epitope is well exposed. On gp120, epitopes on the nonneutralizing face now appear to be buried in the gp41-gp120 interaction. The oligomer is shown as a trimer in line with the oligomerization properties of gp41. For the mature oligomer on the surface of primary viruses, further occlusion of epitopes relative to TCLA viruses results. The only epitopes clearly defined as well exposed on a large fraction of isolates are b12, 2G12 and 2F5. Other epitopes may remain to be discovered.
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