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Title:  Genes of kaposi's sarcoma associated herpesvirus

United States Patent:  6,264,958

Inventors:  Hayward; Gary S. (Baltimore, MD); Nicholas; John (Towson, MD); Reitz; Marvin R. (Derwood, MD); Hardwick; J. Marie (Baltimore, MD)

Assignee:  The Johns Hopkins University (Baltimore, MD)

Appl. No.:  230637

Filed:  November 23, 1999

PCT Filed:  July 24, 1997

PCT NO:  PCT/US97/12931

371 Date:  November 23, 1999

102(e) Date:  November 23, 1999

PCT PUB.NO.:  WO98/04284

PCT PUB. Date:  February 5, 1998

Abstract

A human gamma herpesviris genome known as Kaposi sarcoma associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8) is present in virtually all AIDS and non-AIDS Kaposi's sarcoma (KS) lesions, as well as in body cavity based lymphomas (BCBL), Multiple myeloma, and in multicentric Casdeman's disease. Isolation and DNA sequencing of a 17-kb segment encompassing a HHV-8 divergent locus (DL-B) between ORF11 and ORF17 revealed the presence of nine viral ORFs with gene products related to cellular proteins. These include the complete thymidylate synthase (TS) gene and a dihydrofolate reductase (DHFR) gene, four cytokine genes (vIL6, vMIP-1A, vMIP-1B and BCK) that have not previously been found to be encoded by a virus, and a Bcl2 homologue. This region in HHV-8 also contains the T1.1 abundant lytic cycle nuclear RNA gene and encompasses two genes (or exons) encoding proteins with C4HC3 zinc finger domains of the PHD/LAP subtype. The latter are related to the spliced immediatelady IE1 protein of the bovine gamma-2 class herpesvirus BHV-4 and a similar motif found in HVS ORF12. Transcripts form the IE-1A, IE-1B, DHFR, and MIP-1B genes were all detected by Northern blot hybridization analysis in a BCBL cell line at 12-h after induction with butyrate, but were not present before induction, indicating that these are all primarily lytic cycle genes.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an isolated and purified HHV-8 virally encoded protein.

It is another object of the present invention to provide an antibody preparation which is specifically immunoreactive with an HHV-8 virally encoded protein, but is not immunoreactive with a cellular homologue of the protein.

It is an object of the present invention to provide a polynucleotide which encodes one or more of HHV-8 virally encoded proteins.

Another object of the invention is to provide a polynucleotide probe or primer for detecting HHV-8 virus divergent locus DL-B.

Another object of the invention is to provide a polypeptide which comprises at least 13 contiguous amino acids selected from a HHV-8 virally encoded protein.

Another object of the invention is to provide a method for diagnosing an HHV-8 associated disease, such as Kaposi's sarcoma, Castleman's disease, Multiple myeloma, and Body cavity based large cell lymphoma (BCBL).

Another object of the invention is to provide another method for diagnosing an HHV-8 associated disease.

Still another object of the invention is to provide a method of screening test compounds for candidate drugs for treating HHV-8 infections.

These and other objects of the invention are achieved by providing one or more of the embodiments described below. According to one embodiment of the invention an isolated and purified HHV-8 virally encoded protein is provided. The protein is selected from the group consisting of: TS, DHFR, Bcl-2, IL-6, MIP-1A, MIP-1B, BCK, IE-1A, and IE-1B, as shown in SEQ ID NO: 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively.

According to yet another embodiment of the invention an antibody preparation is provided which is specifically immunoreactive with an HHV-8 virally encoded protein, but is not immunoreactive with a cellular homologue of the protein. The virally encoded protein is selected from the group consisting of: TS, DHFR, Bcl-2, IL-6, MIP-1A, MIP-1B, BCK, IE-1A, and IE-1B, as shown in SEQ ID NO: 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively.

According to still another embodiment of the invention a polynucleotide is provided which encodes one or more of HHV-8 virally encoded proteins. The one or more virally encoded proteins are selected from the group consisting of: TS, DHFR, Bcl-2, IL-6, MIP-1A, MIP-1B, BCK, IE-1A and IE-1B, as shown in SEQ ID NO: 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively. The polynucleotide does not contain HHV-8 genes which are not in the divergent locus DL-B.

In still another embodiment of the invention a polynucleotide probe or primer is provided for detecting HHV-8 virus divergent locus DL-B. The probe or primer comprises at least 12 contiguous nucleotides selected from the group consisting of: SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, and 9.

In yet another embodiment of the invention a polypeptide is provided which comprises at least 13 contiguous amino acids selected from a HHV-8 virally encoded protein. The virally encoded protein is selected from the group consisting of: TS, DHFR, Bcl-2, IL-6, MIP-1A, MIP-1B, BCK, IE-1A, and IE-1B, as shown in SEQ ID NO: 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively.

Also provided by the present invention is a method for diagnosing a HHV-8 associated disease, such as Kaposi's sarcoma, Castleman's disease, Multiple myeloma, and Body cavity based large cell lymphoma (BCBL). The method comprises the steps of:

detecting an HHV-8 viral polynucleotide or protein in a body sample of a patient, wherein presence of an HHV-8 polynucleotide or protein indicates an HHV-8 associated disease, wherein the HHV-8 virally encoded protein is selected from the group consisting of: TS, DHFR, Bcl-2, IL-6, MIP-1A, MIP-1B, BCK, IE-1A, and IE-1B, as shown in SEQ ID NO: 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively, and the HHV-8 polynucleotide is selected from the group consisting of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, and 9.

According to another embodiment of the invention another method is provided for diagnosing an HHV-8 associated disease. The method comprises:

detecting antibodies in the serum of a patient. The antibodies specifically bind to an HHV-8 protein selected from the group consisting of: TS, DHFR, Bcl-2, IL6, MIP-1A, MIP-1B, BCK, IE-1A, and IE-1B, as shown in SEQ ID NO: 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively.

Another embodiment of the invention is a method of screening test compounds for candidate drugs for treating HHV-8 infections. The method comprises:

contacting a test compound with an HHV-8 virally encoded protein selected from the group consisting of: TS, DHFR, Bcl-2, IL-6, MIP-1A, MIP-1B, and BCK, as shown in SEQ ID NO: 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively; and

testing the protein for activity, wherein a test compound which inhibits activity of the protein is a candidate drug for treating HHV-8.

The present invention thus provides the art with a large number of new diagnostic and therapeutic agents for dealing with HHV-8. In addition, it provides the art with targets for development of drugs for treating HHV-8 infections.

Claim 1 of 10 Claims

What is claimed is:

1. A polynucleotide encoding one or more of HHV-8 virally encoded proteins selected from the group consisting of: TS, DHFR, Bcl-2, IL-6, MIP-1A, MIP-1B, BCK, IE-1A, and IE-1B , as shown in SEQ ID NO: 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively, wherein the polynucleotide does not contain HHV-8 genes which are not in the divergent locus DL-B.

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