Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Patent
1994-11-10
2000-03-28
Scheiner, Laurie
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
4242081, 530327, 530328, 530300, A61K 3921
Patent
active
060428317
DESCRIPTION:
BRIEF SUMMARY
The invention concerns epitopes of the HIV virus gp160 protein, that are immunologically homologous to epitopes of the protein family of the human major histocompatibilty complex HLA, to be used for diagnosing and immunization.
Among the mechanisms thought to be responsible of AIDS, it has been suggested that auto-immunity, namely auto-antibody induction mechanism, may play a major role (Hebeshaw J. A and Dalgleish A. G., J. Acquired Immun. Defic. Syndrome, 2, 457, 1989). The homology of portions of virus components with endogenous proteins of the human body could reduce the self-tolerance immunity mechanisms, thus causing the synthesis of antibodies, and activating cytotoxic T lymphocytes.
The gp120 protein is used to produce vaccines for immunization of HIV infection, as a complex with the gp41 protein, such complex being defined as gp160 (ref.).
The PCT Application No. WO89/09618 claims anti-HIV vaccines devoided of gp160 fragments generating HIV-1 infection enhancing antibodies. However, the cited application does not disclose any gp160 epitope able to induce auto-antibodies in HIV-infected subjects.
The PCT Application No. WO92/05196 concerns alloepitopes of HIV gp160 recognized by CD4+T cell receptors, having a three-dimensional structure (.alpha.-helix) similar to the region of the human Major Hystocompatibiliy Complex (MHC). However, also this cited application does not disclose any gp160 epitope able to induce auto-antibodies in HIV-infected subjects.
The inventor previously isolated and described two monoclonal antibodies, M38 and L31, which react with the HIV virus gp160 protein as well as with the class I HLA protein (Beretta et al., Eur. J. Immunol., 17, 1793-1798, 1987; Grassi et al., J. Exp. Med., 174, 53-62, 1980).
The gene coding said cell protein was idendified and sequenced (Grassi et al., J. Exp. Med., 174, 53-2562, 1980)
Therefore it results obvious the need to identify homology regions between HLA and HIV proteins, either for diagnosis purpose in order to identify crossreactive antibodies in the serum of either AIDS patients or HIV vaccinated subjects, and to produce recombinant vaccines.
In the context of this invention, "epitopes" mean fractions of an antigen molecule that are recognized and/or are able to bind a specific antibody; "immunologically homologous epitopes" mean epitopes of at least two different antigen molecules, that are recognized and/or are able to bind the same antibody; "macromolecular structures" mean either cells, or parts thereof, or proteins, or parts, thereof.
The author has analyzed sequences of both HLA and gp160 proteins, and identified immunologically homologous regions. Further tests with synthetic peptides of the HLA heavy chains have allowed to identify more precisely an immunologically homologous region of gp160 and of the heavy chain of class I HLA. This region corresponds to a specific polypeptide segment of the gp160 protein, wherein two minimum epitope sequences have been defined. The immunologically homologous regions on HLA and the minimum sequence of the epitopes have been identified too.
In the gp 160 protein, said epitopes are separated by a 9 amino acid intervening sequence which is shown not to be immunogenic in the context of the natural gp160 protein, in HIV infected subjects. However, experiments published by Helseth et al. (Journ of Virol. 65, 2119-2123, 1991) showed that 5 of said 9 residues are essential to the maintenance of the quaternary structure of the HIV envelope, since single amino acid substitutions within these positions result in a high dissociation rate between gp120 and gp41. The author of the present invention has also determined that said sequence may be able to induce anti-HIV neutralizing antibodies, when used without its natural flanking sequences.
Therefore an object of this invention are epitopes of the HIV gp160 protein which are chains .alpha.-1 domain protein which is comprised in the following sequence:
According to a preferred embodiment said epitopes are comprised in the region having the following amino acid
REFERENCES:
patent: 4943628 (1990-07-01), Rosen et al.
Grassi et al., 1991, "Human immunodeficiency virus type 1 gp120 mimics a hidden monomorphic epitope borne by class I major histocompatibility complex heavy chains", J. Exp. Med. 174:53-62.
Nara et al., 1991, "Neutralization of HIV-1: a paradox of humoral proportions", FASEB J. 5:2437-2455.
Brolidan et al., 1992, "Identification of human neutralization-inducing regions of the human immunodeficiency virus type 1 envelope glycoproteins", Proc. Natl. Acad. Sci. USA 89:461-465.
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"Preferential V.beta. Usage by Cytotoxic T Cells Cross-Reactive between Two Epitopes of HIV-1 gp160 and Degenerate in Class I MHC Restriction" by Shirai et al. The Journal of Immunology, vol. 151, pp. 2283-2295, No. 4, Aug. 15, 1993.
"Identification of human neutralization-inducing regions of the human immunodeficiency virus type 1 envelope glycoproteins" by Broliden et al. Proc. Natl. Acad. Sci. USA; Immunology, vol. 89, pp. 461-465, Jan. 1992.
"Fine Specificity of the Murine Antibody Response to HIV-1 gp160 Determined by Synthetic Peptides which Define Selected Epitopes" by Wolf et al., Molecular Immunology, vol. 29, No. 7/8, pp. 989-998, 1992.
"Human Immunodeficiency Virus Type 1 gp120 Mimics a Hidden Monomorphic Epitope Borne by Class I Major Histocompatibility Complex Heavy Chains" by Grassi et al. J. Exp. Med. 174, pp. 52-62, 1992.
"Neutralization of HIV-1: a paradox of humoral proportions" by Nara et al., The FASEB Journal, vol. 5, Jul. 1991; pp. 2437-2455.
Contents The Journal of Experimental Medicine, vol. 170, No. 6, Dec. 1, 1989, pp. 2022-2035; "Structural Requirements for Class I MHC Molecule-Mediated Antigen Presentation and Cytotoxic T Cell Recognition of an Immunodominant Determinant of the Human Immunodeficiency Virus Envelope Protein" by Takahashi et al.
"AIDS Forchung" by Nick et al., 1991 6: 46; pp. 467-473.
Palker et al., 1989, J. Immunol. 142: pp. 3612-3619.
Beretta et al., 1987, Eur. J. Immunol. 17: pp. 1793-1798.
Hildreth Ronald B.
La Fondation Mondiale Recherche et Prevention Sida
Parkin Jeffrey S.
Scheiner Laurie
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