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Stabilized primate lentivirus envelope glycoproteins
| Details |
Inventors: Sodroski, Joseph G; Wyatt, Richard T.; Kwong, Peter D.; Hendrickson, Wayne A.; Farzan, Michael;
Assignee: Dana-Farber Cancer Institute, Inc. (Boston, MA) The Trustees of Columbia University in the City of New York (New York, NY)
Primary Examiner: Parkin; Jeffrey S.
Assistant Examiner:
Attorney, Agent or Firm: Nixon Peabody LLP
A modified polypeptide corresponding to an envelope glycoprotein of a primate lentivirus is described. The polypeptide has been modified from the wild-type structure so that it has cysteine amino acid residues introduced to create disulfide bonds, a cavity is filled with hydrophobic amino acids, a Proresidue is introduced at a defined turn structure of the protein, or the hydrophobicity is increased across the interface between different domains, while retaining the overall 3-dimensional structure of a discontinuous conserved epitope of the wild-type protein. Preferably, the polypeptide has more than one of those characteristics. Preferably, the primate lentivirus is HIV, and the protein is HIV-1 gp120. |
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DETAILED DESCRIPTION OF THE INVENTION We have discovered a series of novel polypeptides that can (1) enhance the immunogenicity of primate lentivirus envelope proteins for certain conserved epitopes, (2) generate a greater range of antibodies against "masked" gp120 structures and/or (3) stabilize the three-dimensional structure of the molecule.
We have discovered regions where disulfide bonds can be inserted which will stabilize the conformation of the molecule in a conformation approximating the native envelope glycoprotein conformation.
We have discovered conserved regions and epitopes that are critical for CD4 and chemokine receptor binding.
We have discovered critical turn structures of the molecules as well as internal cavities that decrease the immunogenicity of epitopes that would raise antibodies that could block CD4 binding and/or chemokine binding.
Preferably, the envelope protein is selected from the group consisting of HIV or SIV.
More preferably, it is HIV.
Still more preferably, it is HIV-1 gp120.
We have succeeded in growing crystals of gp120 (from the HXBc2 HIV-1 strain) in a ternary complex with two-domain CD4 (D 1 D2 sCD4) and the Fab fragment of a CD4i neutralizing antibody, 17b Fab.
The crystals diffracted to a minimum Bragg spacing of at least 2.
2A, and data have been collected from cryogenically preserved crystals on the native complex as well as on isomorphous heavy atom derivatives.
While some elements of the HIV-1 gp120 structure (e.
g.
the V3 loop) are not supplied by analysis of these crystals, the vast majority of the gp120 residues are able to be defined in the structure.
Importantly, all of the gp120 residues thought to contribute to the CD4BS and CD4i neutralization epitopes are defined in the available structure.
Many of the antibody responses elicited against the HIV-1 envelope glycoproteins during natural infection of humans are incapable of neutralizing the virus.
Studies of monoclonal antibodies derived from HIV-1-infected individuals indicate that most of these non-neutralizing antibodies are directed against elements of the gp120 and gp41 glycoproteins that interact on the assembled oligomer
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