Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1997-12-23
1999-11-30
Stucker, Jeffrey
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
424 934, 4241841, 4241881, 4242041, 4242081, 530328, 530350, 4352351, 536 2372, C07K 1600, A61K 4900, A61K 3804, C12N 700
Patent
active
059945168
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to mutated proteins encoded by a mutated env gene of a lentivirus, and in particular FIV, HIV or CAEV, to peptide fragments included in the said mutated proteins, to expression vectors expressing the said mutated proteins and to their applications.
Feline immunodeficiency is due to a lentivirus, the feline immunodeficiency virus (FIV), which has a genetic structure similar to that of the lentiviruses of primates (HIV and SIV).
A number of fragments have been selected and have allowed the development of sensitive and specific tests for the detection of seropositive animals, as described in European Patent Applications No. 0,564,477 of Nov. 20, 1991, No. 0,577,458 of Jun. 16, 1993, and French Patent Application No. 94 07062 of Jun. 9, 1994, in the name of the applicant, and are derived, for the majority, from the Env protein of FIV, comprising 854 amino acids, whose sequence is described in European Application 0,577,458, which provides, after cleavage, 2 glycoprotein fragments called SU (surface glycoprotein) and TM (transmembrane glycoprotein).
In particular, the TM protein includes several fragments of interest, namely: corresponds to positions 595-647 of the Env protein of FIV, corresponds to positions 681-711 of the Env protein of FIV, the said fragment contains an epitope including the sequence: Cys.sup.697 --Asn--Gln--Asn--Gln--Phe--Phe--Cys--Lys.sup.705 (peptide called P237), corresponds to positions 744-788 of the Env protein of FIV, and corresponds to positions 826-854 of the Env protein of FIV.
Whereas in the field of detection, there are now available a range of reagents for the detection of FIV, in the field of immunoprotection, it has appeared that the principal immunodominant domain (PID) of the FIV envelope protein, comprising the abovementioned peptide P237, can cause the formation of antibodies which facilitate viral infection, whose action has a deleterious effect opposite that of the protective antibodies generated by vaccination with the Env protein (J. R. MASCOLA et al., AIDS Research & Human Retroviruses, 1993, 9, 12, 1175-1184).
In addition, a complete and mature envelope protein, in its oligomeric form, is preferable for inducing the formation of antibodies directed against conformation epitopes, among which are neutralizing antibodies (C. C. BRODER et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 11699-11703).
It has appeared that the elimination and replacement of the Cys residues from the PID causes an envelope maturation defect which is no longer presented in its mature form at the surface of the infected cells (SYU W. J., 1991, J. Virol., 65, 6349-6352, DEDERA et al., J. Virol., 1992, 66, 1207-1209).
The two neighbouring cysteine residues of the peptide P237, conserved in the ectodomain of the TM, in most retroviruses, define a loop structure which is the major constituent of the PID. The amino acid sequence between the two cysteine residues is highly conserved in the same species of lentivirus, such as FIV or HIV. On the other hand, when the various species of lentivirus, for example HIV-1 and FIV, are compared, although the two cysteine residues are conserved, the amino acid sequences situated between these two residues do not exhibit any homology (FIG. 1A).
As regards HIV, the Principal Immunodominant Domain (PID) of the envelope of the human immunodeficiency type 1 virus (HIV-1) is highly conserved among the various viral isolates of HIV-1. The sequence between the two cysteines of the PID is also conserved among the HIV-1 subtypes, except for the 0 subtype (Outsider), which could correspond to a new type of HIV-1. The PID sequence of HIV-1 is completely different from that of HIV-2, which is, on the other hand, identical to that of the simian immunodeficiency virus (SIV), to which HIV-2 is phylogenetically related.
In general, the PID of lentiviruses can cause the formation of viral infection facilitating antibodies whose action has a deleterious effect opposite that of the protective antibodies generated by vaccination with the Env protein, as sp
REFERENCES:
patent: 5648209 (1997-07-01), Avrameas et al.
Fox, J. L., No winners against AIDS, Bio/Technology, vol. 12, p. 128, see entire page, Feb. 1994.
Fahey et al., Status of immune-based therapies in HIV infection and AIDS, Clin. exp. Immunol. vol. 88, pp. 1-5, see page 3, second col., third full paragraph, Jan. 1992.
Pancino Gianfranco
Sonigo Pierre
Centre National de la Recherche Scientifique--CNRS
Park Hankyel T.
Stucker Jeffrey
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