Research Interests

Molecular biology of herpesviruses that infect man; the use of viral vectors in gene therapy and vaccination. Study the herpes simplex viruses HSV-1 and HSV-2 which cause facial and genital infections, and the human Herpesviruses 6 and 7 (HHV-6 and HHV-7) which cause mild to life threatening diseases in children and in bone marrow and kidney transplantations .

Current research projects:

Studies in the laboratory concentrate on (i) Molecular mechanisms of herpesvirus replication and gene expression (ii) Disease associations of the lymphotropic Human herpesviruseses 6A, 6B and 7 (HHV-6A, HHV-6B and HHV-7). (iii) Derivation of herpesvirus vectors towards their use in gene therapy and vaccination.

Molecular Virology: Studies of viral DNA replication and packaging; Virus-host cell interactions including HSV-1 host shutoff by mRNA degradation; HHV-6A & HHV-6B induced cell stress and suicidal functions leading to apoptosis; alternations of cellular pathways and cell cycle arrest; activation of immune response in viral infections; viral miRNAs.

Disease association: Collaborative studies with clinical centers concerning life threatening HHV-6B reactivation in bone marrow and kidney transplantations; Infections in children with central nervous system complications.

Gene therapy: Development of HSV vectors for gene therapy of brain tumors employing mouse model systems; HHV-6 vectors for Leukemia/lymphomas; HHV-6 vectors towards potential vaccination against HSV infection and HIV-1/AIDS; development of anti-cancer vaccination.

Recognition for scientific contributions :

· Discovery of the human herpesvirus 7 (HHV-7). The virus is one of 8 different herpesviruses that infect man. HHV-7 causes grave febrile convulsions in children and it is tested in patients by medial laboratories worldwide. It is studied molecularly by many virologists.

· First distinction between Human Herpesviruses 6A and 6B by DNA structure, epidemiology and disease association.

· Recognition of the universal signals necessary for herpesvirus DNA packaging in the structural infectious virions.

· Derivation of the Herpesvirus amplicon vectors, which are now employed worldwide in gene and cell therapy.

· Identification and characterization of the virion host shutoff (vhs) mRNAse controlling both host and viral gene expression.

Patents :

Methods of detecting the presence of human herpesvirus-7 infection U.S. Patent 5230997 . The invention relates to the discovery of human herpesvirus-7 (HHV-7). The invention also relates to bioassays for the diagnosis of HHV-7 and its detection in biological samples and to a vaccine against human herpesvirus-7. American patent granted.

Lymphotropic agents and vectors. U.S. Patent 6503752. The invention relates to amplicon vectors with an HHV-6 or HHV-7 DNA replication origin, a cleavage/ packaging signal, a promoter sequence which induces expression in T cells and foreign nucleic acid sequences, exemplified by the HSV-1 Thymidine Kinase, glucocerebrosidase, insulin growth factor and antisense sequence to an oncogene active in malignant lymphatic cells. US Patent granted.

Additional patent applications under review:

1. Composite oncolytic herpes virus vectors- WO 02/087625 Patent No./Publication No. US-2004-0120928 .  

2. Vaccination vectors derived from lymphotropic human herpes viruses 6 and 7- WO 2005/012539 EP 1660666 US-2007-0264281.

3. Production of BAC Vectors Carrying Viral Genomes- International Procedure Application No. IL2008/001412 Patent No./Publication No. WO 2009/053988, U.S.A. App. No. 60/982,625 .

Selected Publications

Selected Publications

(out of 92 publications)

1. Niza Frenkel, Ronen Borenstein and Haim Zeigerman. Selected aspects of Herpesvirus DNA replication, cleavage/packaging and the development and use of viral amplicon vectors. Book: “From the Hallowed Halls of Herpesvirology”, John A. Blaho and Joel D. Baines Editors, World Scientific Publishing / Imperial College Press , 2010, in press.

2. Borenstein R, Zeigerman H, Frenkel N . The DR1 and DR6 first exon of Human Herpesvirus 6A (HHV-6A) are not required for virus replication in culture and are found deleted in virus stocks which replicate well in T cell lines. J. Virol. 84 (6) : 2648-2656, 2010.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826055/pdf/1951-09.pdf

3. Borenstein R, Frenkel N. Cloning human herpes virus 6A genome into bacterial artificial chromosomes and study of DNA replication intermediates. Proc. Natl. Acad. Sci. USA 106: 19138–19143, 2009.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2767366/pdf/zpq19138.pdf

4. Mlechkovich G , Frenkel N . Human herpesvirus 6A (HHV-6A) and HHV-6B alter E2F1/Rb pathways and E2F1 localization and cause cell cycle arrest in infected T cells. J. Virol.;81 (24) : 13499-508.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17913805

5. Frenkel N , Borenstein R . Characterization of the Lymphotropic Amplicons-6 and Tamplicon-7 Vectors Derived from HHV-6 and HHV-7.Curr Gene Ther. 6 (3) :399-420, 2006.

http://www.ingentaconnect.com/content/ben/cgt/2006/00000006/00000003/art00012?token=00531b76d1a3dc0a69f582a2f4876753375686f4957275c277b422c316756766634247b2e6e60e6921d

6. Frenkel N . The History of the HSV Amplicon: From Naturally Occurring Defective

Genomes to Engineered Amplicon Vectors. Curr Gene Ther.6 (3) :277-301, 2006.

http://www.ingentaconnect.com/content/ben/cgt/2006/00000006/00000003/art00002?token=004b14750660582a2f4876753375686f4957275c277b422c316756766634247b6e6e6d4ca67

7. Barzilai A , Zivony-Elbom I , Sarid R , Noah E , Frenkel N .The herpes simplex virus type 1 vhs-UL41 gene secures viral replication by temporarily evading apoptotic cellular response to infection: Vhs-UL41 activity might require interactions with elements of cellular mRNA degradation machinery.

J. Virol.;80 (1) :505-13, 2006.

http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=16352574

8. Borenstein R , Singer O , Moseri A , Frenkel N . Use of amplicon-6 vectors derived from human herpesvirus 6 for efficient expression of membrane-associated and -secreted proteins in T cells.J Virol.78 (9) :4730-43, 2004.

http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=15078955

9. Rappaport D , Engelhard D , Tagger G , Or R , Frenkel N . Antiviral prophylaxis may prevent human herpesvirus-6 reactivation in bone marrow transplant recipients. Transpl Infect Dis. 4: 10-16, 2002.

http://www.blackwell-synergy.com/doi/abs/10.1034/j.1399-3062.2002.040101.x

10. Romi H , Singer O , Rapaport D , Frenkel N .Tamplicon 7, a novel T lymphotropic vector derived from human herpesvirus 7. J. Virol. 73: 7001-7007,1999.

http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=10400799

11. Katsafanas, G.C., Schirmer, E.C., Wyatt, L.S. and Frenkel, N. In vitro activation of human herpesviruses 6 and 7 from latency. Proc. Natl. Acad. Sci. 93: 9788-9792, 1996.

http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=8790409

12. Frenkel, N., Singer, O. and Kwong, A.D. The herpes simplex virus amplicon - a versatile defective virus vector. Gene Therapy. 1: S40-S46, 1994.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed

13. Wyatt L S, Frenkel N.Human herpesvirus 7 is a constitutive inhabitant of adult human saliva.J Virol. 66 (5) :3206-9, 1992.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=1348548&query_hl=12&itool=pubmed_DocSum

14. Schirmer E C, Wyatt L S, Yamanishi K, Rodriguez W J, Frenkel N. Differentiation between two distinct classes of viruses now classified as human herpesvirus 6.
Proc Natl Acad Sci U S A. 1;88 (13) :5922-6, 1991.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=1648234&query_hl=12&itool=pubmed_DocSum

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=2173796&query_hl=12&itool=pubmed_DocSum

15. Wyatt L S, , Balachandran N, and Frenkel N .Variations in the replication and antigenic properties of human herpesvirus 6 strains.J Infect Dis.;162 (4) :852-7, 1990.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=2169499&query_hl=12&itool=pubmed_DocSum

16. Frenkel, N., E.C. Schirmer, Wyatt L,. S. Katsafanas G, Roffman, E., Danovich R.M. and

June, C.H. Isolation of a new herpesvirus from human CD4+ T cells. Proc. Natl. Acad. Sci. USA. 87: 748-752, 1990.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=2153965&query_hl=12&itool=pubmed_DocSum

17. Frenkel N, Schirmer E C, Katsafanas G, and June C H. T-cell activation is required for

efficient replication of human herpesvirus 6.J Virol. Sep;64 (9) :4598-602, 1990.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=2166835&query_hl=12&itool=pubmed_DocSum

18. Danovich RM , Frenkel N . Herpes simplex virus induces the replication of foreign DNA.
Mol Cell Biol. 8 (8) :3272-81, 1988.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=2850486&query_hl=12&itool=pubmed_DocSum

19. Kwong AD , Kruper JA , Frenkel N .Herpes simplex virus virion host shutoff function.
J Virol.;62 (3) :912-21, 1988.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=2828686&query_hl=12&itool=pubmed_DocSum

20. Strom T , Frenkel N . Effects of herpes simplex virus on mRNA stability.
J Virol.;61 (7) :2198-207, 1987.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=3035220&query_hl=12&itool=pubmed_DocSum

21. Kwong AD , Frenkel N . Herpes simplex virus infected cells contain function (s) which destabilize both host and viral mRNAs. Proc. Natl. Acad. Sci. USA. 84: 1926-1930, 1987.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=3031658&query_hl=12&itool=pubmed_DocSum

22. Deiss LP , Chou J , Frenkel N . Functional domains within the a sequence involved in the cleavage-packaging of herpes simplex virus DNA.J Virol.;59 (3) :605-18, 1986.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=3016323&query_hl=12&itool=pubmed_DocSum

23. Deiss LP , Frenkel N . Herpes simplex virus amplicon: cleavage of concatemeric DNA is linked to packaging and involves amplification of the terminally reiterated a sequence.
J Virol.;57 (3) :933-41, 1986.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=3005637&query_hl=12&itool=pubmed_DocSum

24. Kwong AD , Frenkel N . The herpes simplex virus amplicon. IV. Efficient expression of a chimeric chicken ovalbumin gene amplified within defective virus genomes.
Virology. 30;142 (2) :421-5, 1985.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=2997994&query_hl=12&itool=pubmed_DocSum

25. Spaete RR , Frenkel N . The herpes simplex virus amplicon: analyses of cis-acting replication functions.Proc Natl Acad Sci U S A.;82 (3) :694-8, 1985.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=2983310&query_hl=12&itool=pubmed_DocSum

26. Read GS , Frenkel N . Herpes simplex virus mutants defective in the virion-associated shutoff of host polypeptide synthesis and exhibiting abnormal synthesis of alpha (immediate early) viral polypeptides.J Virol.;46 (2) :498-512, 1983.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=6302315&query_hl=12&itool=pubmed_DocSum

27. Spaete RR , Frenkel N . The herpes simplex virus amplicon: A new eukaryotic defective-virus cloning-amplifying vector. Cell 30: 295-304, 1982.