By current estimates 25-35% of all human cancers are of viral origin or require viral infection as an essential cofactor. The goal of our research is to understand viral tumorigenesis; specifically, cancers that are caused by Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8). KSHV is a double-stranded DNA virus of about 120kbp, which belongs to the rhadinovirus family of human herpesviruses. It was discovered in 1994 and is associated with Kaposi’s sarcoma (KS) as well as B-cell lymphoproliferative diseases: pleural effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD). These diseases are ultimately fatal as they affect internal organs and, in the U.S., are seen in the context of immune suppression such as HIV-positive individuals or transplant patients.

(1) Transcriptional profiling of AIDS-associated cancers
To determine the contribution of viral genes in AIDS-associated cancers, we have developed real-time quantitative PCR-based arrays, which allow us to analyze patterns of all KSHV transcripts in PEL and KS (Cancer Research 63:2010pp (2003)). Using this technology, we have designed viral arrays for all human herpesviruses. In collaboration with physicians and researchers at the UNC Lineberger Comprehensive Cancer Center, with the NCI—AIDS malignancy clinical trials consortium, the NCI intramural viral epidemiology group, the Memorial Sloan-Kettering Cancer Center and the University of Miami cancer center, we are using this approach to determine the transcriptional responses of EBV and KSHV-associated lymphomas to novel anti-cancer regimens in culture, in mouse models and in patients.

(2) Identification of new viruses
Based on our expertise in high-throughput PCR, we are trying to identify novel viruses in the human population. To test our strategy, we use baboons and, to date, have identified a novel primate KSHV homolog in baboons (J.Virol.77: 8159pp (2003)) as well as a novel SV40 homolog. We have since established the bioinformatics and robotics infrastructure for rapid screening and quantification of virtually all known viruses. Using this approach, we have identified novel West-Nile viruses (J.Clin.Microbio 43:1511pp (2004)) and are now studying West-Nile inhibitors and novel vaccines.

(3) Basic mechanisms of viral gene regulation
We demonstrated that the KSHV latency associated nuclear antigen (LANA) is transcribed in every single KS tumor cell. Hence, we surmise that LANA is essential for KS tumorigenesis. LANA is required for latent viral replication and proper episome segregation. LANA also binds to the p53 and Rb tumor suppressor proteins, which suggests that LANA might be a putative viral oncogene and may contribute to KSHV pathogenesis. Since the LANA promoter is the major latency promoter of KSHV, we are engaged in a detailed investigation of its architecture and regulation by cellular factors, such as p53, Sp1 as well as LANA itself (J.Biol.Chem. 279:16822pp (2004)).

(4) Mouse models of KSHV oncogenesis
We have developed transgenic mice, which express the LANA protein under the control of its own promoter and had previously shown that the LANA promoter exhibits B-lineage specificity in transgenic mice (J.Virol 76:11024pp (2002)). Offspring from multiple independent founder animals develope follicular B-cell proliferative disorders. Thus, our lab has established the first in vivo model for KSHV LANA-dependent tumorigenesis.

Building upon or initial studies of SCID-human mouse models for primary KSHV infection (J.Exp.Med. 190:1857pp (1999)), we established a xenograftmodel for KSHV-associated lymphomas. Using this model we are investigating the anti-lymphoma properties of established and novel anti-viral drugs (Cancer Research 64:4790pp (2004)).
In sum, our cancer-related efforts seek to combine translational studies on KSHV-associated cancers with appropriate mouse models and the detailed molecular investigation of a few key viral oncogenes. Using high-throughput real-time quantitative PCR as the signature technology platform for this group we are able to rapidly cross-validate the results of these three approaches to cancer research.

D. Dittmer, C. Stoddart, R. Renne, V. Linquist-Stepps, C. Bare, J.M. McCune and D. Ganem, ”Experimental Transmission of Kaposi’s Sarcoma-Associated Herpesvirus (KSHV/HHV-8) to SCID-hu Thy/Liv Mice ”, J. Exp. Med. 190, 1857-1868 (1999)

J. Jeong, J. Papin and D. Dittmer “Differential Regulation of the overlapping Kaposi’s Sarcoma-associated Herpesvirus (KSHV/HHV-8) vGCR (orf74) and LANA (orf73) promoter”, J. Virology 75, 1798-1807 (2001)

F. Fakhari and D. Dittmer, “Charting latency genes by whole genome real-time quantitative RT-PCR in Kaposi’s Sarcoma-associated Herpesvirus (KSHV/HHV-8)”, J. Virology 76, 6213-6223 (2002)

J. Jeong, R. Hines-Boykin, JD. Ash and D. Dittmer “Kaposi’s sarcoma-associated Herpesvirus (KSHV) latent nuclear antigen (LANA/orf73) promoter shows B-lymphocyte and endothelial-specificity in transgenic mice”, J. Virology 76, 11024-11032 (2002)

R. Renne, D. Dittmer, D. Kedes, K. Smith, R. Desrosiers, P.A. Luciw, D. Ganem, ”Experimental Transmission of Kaposi’s Sarcoma-associated Herpesvirus (KSHV/HHV-8) to SIV-positive and SVI-negative Rhesus macaques”, J. Medical Primatology 33, 1-9 (2004)

D. Whitby, A. Stossel, C.D. Wang, C.Gamache, J. Papin, M. Bosch, A. Smith, D. Kedes, G. White, RC. Kennedy and D.P. Dittmer, “A novel Kaposi’s Sarcoma-associated herpesvirus (KSHV/HHV-8) homolog in Baboons”, J. Virology 77, 8159-8165 (2003)

D.P. Dittmer “ Transcription of Kaposi’s Sarcoma-associated herpesvirus in Kaposi’s Sarcoma lesions”, Cancer Research 63, 2010-2015 (2003)

J.F. Papin, W. Vahrson, and D.P. Dittmer. “SYBR-based real-time quantitative PCR for West Nile Virus circumvents potential false negative results due to strain variability”, J. Clinical Microbiology 43, 1511-1518 (2004)

B. Damania, J.H. Jeong, B. Bowser, S. DeWire M. Staudt and D. P. Dittmer “A Functional Comparison of Rta Transactivator Proteins of Gamma-2 Herpesviruses”, J. Virology 78, 5491-5499 (2004)

J. H. Jeong, J. Opela, W. Kim, C. McMurtry, R. Renne, D.P. Dittmer “Regulation of the core promoter for the latency-associated nuclear antigen (LANA) of Kaposi’s Sarcoma-associated herpesvirus”, J. Biological Chemistry 279, 16822-16831 (2004)

M.R. Staudt, Y. Kanan, J.H. Jeong, J.F. Papin, R. Hines-Boykin, D.P. Dittmer “The tumor microenvironment controls primary effusion lymphoma growth in vivo”, Cancer Research 64(14), 4790-9 (2004)

R.A. Floyd, J.E. Schneider, Jr., and D.P. Dittmer “Methylene Blue Photoinactivation of RNA Viruses”, Antiviral Research 61(3), 141-51 (2004)

D.P. Dittmer, W. Vahrson M. Staudt, J. Papin, R. Hines-Boykin and F. Fakhari “Real-time quantitative PCR arrays for virally associated cancers”, Cancer Genomics and Proteomics 1, 117-124 (2004)

T. Kalina, H. Lu, Z. Zhao, E. Blewett, D.P. Dittmer, J. Randolph-Habecker, D. G. Maloney, R. G. Andrews, H.-P. Kiem, J. Storek, “De novo generation of CD4 T cells against viruses present in the host during immune reconstitution”, Blood 105, 2410-2414 (2005)

D.P. Dittmer, W. Vahrson, M. Staudt, C. Hilscher, F.D. Fakhari, “Kaposi’s Sarcoma in the era of HAART—An update on mechanisms, diagnostics and treatment”, AIDS Rev. 7(1):56-61 (2005)

D.P. Dittmer, C. M. Gonzalez, W. Vahrson, S.M. DeWire and B. Damania, “Whole-Genome Transcription Profiling of Rhesus Monkey Rhadinovirus (RRV)”, J. Virology, in press (2005)

M. Kurokawa, S.K. Ghosh, J.C. Ramos, A.M. Mian, N. L. Toomey, L. Cabral, D. Whitby, G.N. Barber, D.P. Dittmer, and W.J. Harrington, Jr., “Azidothymidine inhibits NF-kB and induces Epstein-Barr virus gene expression in Burkitt’s lymphoma”, Blood, in press (2005)

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