Chemistry: molecular biology and microbiology – Virus or bacteriophage – except for viral vector or...
Patent
1995-08-14
1999-11-09
Achutamurthy, Ponnathapura
Chemistry: molecular biology and microbiology
Virus or bacteriophage, except for viral vector or...
4353201, 435 693, 435372, 4242081, 4241881, 530350, 536 2372, A61K 3921, C07K 14155, C12N 510
Patent
active
059812583
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a composition resulting from the combination of trans-dominant variants of two viral proteins originating from the same virus. The combination of these two variants enables a resistance to infection by or propagation of the virus in question to be conferred. The present invention finds an advantageous application in the treatment or prevention of infections caused by HIV (human immunodeficiency virus) responsible for AIDS (acquired immunodeficiency syndrome).
In the context of the search for and preparation of medicinal products that inhibit viral infections, somatic gene therapy by intracellular immunization constitutes one of the promising approaches for the future. This concept, defined by Baltimore (1988, Nature, 335, 395-396), consists in genetically modifying cells so as to cause them to synthesize a nucleic acid or a heterologous protein endowing them with resistance against the viral infection. One of the possible approaches for acquiring this resistance is to cause the host cell to synthesize genes that inhibit a step of the viral cycle. Although all the steps of the viral cycle may be targeted in order to implement such a therapy, the genes participating in an early step constitute a potentially advantageous target. Such is the case with the tat and rev genes of the HIV virus, which play an essential part in initiation of the viral replication.
The tat gene codes for a TAT protein which transactivates the expression of all of the genes of HIV (Arya et al., 1985, Science, 229, 69-73). It appears that TAT participates at both transcriptional and post-transcriptional level. It interacts specifically with a short nucleotide sequence localized at the 5' end of the genome and of the viral transcripts and designated TAR (standing for trans-activation responsive region) sequence (Rosen et al., 1985, Cell, 41, 813-823).
The REV protein, the expression product of the rev gene, promotes the transport of large-sized messenger RNA (mRNA) to the cytoplasm, to be translated therein. For its part, REV specifically recognizes an RRE (standing for REV responsive element) sequence on the mRNA. This sequence is localized in proximity to another sequence termed CRS (cis-acting repression sequence), involved in the nuclear retention of the mRNA carrying it. It is assumed that binding of the REV protein to its RRE target sequence has the effect of counterbalancing the inhibitory effect of CRS on the passage of large viral mRNA into the cytoplasm.
Although their expression products are very different from a molecular mass, sequence and mechanism of action standpoint, regulator genes exerting a function similar to TAT and/or REV have been identified in the genome of other infectious viruses, such as HTLV-I and -II (human T-cell leukemia virus) retroviruses responsible for severe forms of leukemia and herpesviruses (chicken pox, shingles and Epstein-Barr viruses).
For some years, negative and dominant (transdominant) mutants of these various viral proteins have been described in the literature. In particular, several teams have generated trans-dominant variants of the TAT and REV proteins capable of binding to their target sequence but incapable of exerting the function of the native protein. While their inhibitory effect with respect to the action of the native protein has been demonstrated, their efficacy in HIV-infected cells nevertheless remains to be determined.
It has now been found that the expression in an HIV-infected cell of at least two genes coding for transdominant variants of the TAT and REV proteins, respectively, of the HIV virus enables propagation of the virus to be blocked. The authors have demonstrated that the inhibition of viral infection resulting from the joint expression of the two genes is markedly greater than that observed on expression of either one of these genes. This synergistic effect constitutes an unexpected advantage.
The objective of the present invention is to make available to the public an especially effective pharmaceutical composition, and which is
REFERENCES:
Haynes et al. Ann. Med., Trends in Molecular Medicine, vol. 28, pp. 39-41, 1996.
Plavec et al. Gene Therapy, vol. 4, pp. 128-139, 1997.
Fox "No Winner against AIDS" Bio/Technology vol. 12, Feb. 1994, p. 128.
Feinberg et al. "Intracellular Immunization: Trans-dominant Mutants . . . " AIDS Res. and Human Retroviruses vol. 8, No. 6, 1992, pp. 1013-1022.
Liem et al. "The Development and Testing of Retroviral Vectors . . . " Human Gene Therapy, vol. 4, No. 5, Oct. 1993, pp. 625-634.
Rosen "Tat and Rev: positive modulators of human . . . " Gene Expression vol. 1, No. 2, May 1991, pp. 85-90.
Pearson et al, "A transdominant tat mutant that inhibits . . . " PNAS, USA vol. 87, No. 13, Jul. 1990, pp. 5079-5083.
Bevec et al. "Inhibition of human immunodeficiency virus . . . " PNAS, USA vol. 89, No. 20, 1992, pp. 9870-9874.
Journal of Virology, vol. 67, No. 6, Jun. 1993, pp. 3199-3207, Bahner et al, "Comparison of Trans-Dominant Inhibitory Mutant Human Immunodeficiency Virus Type 1 Genes Expressed by Retroviral Vectors in Human T Lymphocytes".
J. Lisziewicz et al., "Efficacy of antitat Gene Therapy in the Presence of High Multiplicity Infection and Inflammatory Cytokines," Human Gene Therapy, 7:2209-2216, Dec. 1, 1996.
M. Bonyhadi et al., "RevM10--Expressing T Cells Derived in Vivo from Transduced Human Hematopoietic . . .", Journal of Virology, vol. 71, No. 6, pp. 4707-4716, Jun. 1997.
U. Ranga et al., "Enhanced T cell engraftment after retroviral delivery of an antiviral gene in HIV-infected individuals," Proc. Natl. Acad. Sci. USA, vol. 95, pp. 1201-1206, Feb. 1998.
M.C. Poznansky, "Inhibition of human immunodeficiency virus replication . . .", Human Gene Therapy, 9:487-496, Mar. 1998.
Ulich et al., "Inhibition of human immunodeficiency virus type 1 replication is enhanced . . .," J. Virol, 70(7):4871-4876, Jul. 1996 (Abstract).
Akkina et al., "Modeling Human Lymphoid Precursor Cell Gene Therapy in the SCID-hu Mouse," Blood, 84(5):1393-1398 (1994).
Cournoyer, "Gene Therapy Of The Immune System," Annu Rev. Immunol., 11:297-329 (1993).
Gilboa et al., "Gene therapy for infectious diseases: the AIDS model," Trends in Genetics, 10(4) 139-144.
Green et al., "Mutational Analysis of HIV-1 Tat Minimal Domain Peptides: Identification of Trans-Dominant Mutants That Suppress HIV-LTR-Driven Gene Expression," Cell 58:215-223 (1989).
Haynes, "Scientific and Social Issues of Human Immunodeficiency Virus Vaccine Development," Science, 260:1279-1286 (1993).
Johnston et al., "Present Status and Future Prospects for HIV Therapies," Science 260:1286-1293 (1993).
Ledley, "Clinical Considerations in the Design of Protocols for Somatic Gene Therapy," Human Gene Therapy, 2:77-83 (1991).
Mitsuya et al., "Strategies for antiviral therapy in AIDS," Nature, 325:773-778 (1987).
Orkin et al., "Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy," Dec. 7, 1995.
Rice et al., "Mutational Analysis of the Conserved Cysteine-Rich Region of the Human Immunodeficiency Virus Type 1 Tat Protein," Journal of Virology, 64(4):1864-1868 (1990).
Venkatesh et al., "Mutants in a Conserved Region near the Carboxy-Terminus of HIV-1 Rev Identify Functionally Important Residues and Exhibit a Dominant Negative Phenotype," Virology, 178:327-330 (1990).
Woffendin et al., "Expression of a protective gene prolongs survival of T cells in human immunodeficiency virus-infected patients," Proc. Nat'l. Acad. Sci. USA, 93:2889-2894 (1996).
Guss Tania
Mehtali Majid
Achutamurthy Ponnathapura
Bui Phuong T.
Transgene S.A.
LandOfFree
Composition of trans-dominant variants of viral proteins for obt does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Composition of trans-dominant variants of viral proteins for obt, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Composition of trans-dominant variants of viral proteins for obt will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1454467