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 such as 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.
- 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 Res. 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.
- 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 42:1511pp (2004)) and are now studying West-Nile inhibitors and novel vaccines.
- 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)).
- Mouse models of KSHV oncogenesis. We have developed transgenic mice which express the LANA protein under the control of its own promoter and have previously shown that the LANA promoter exhibits B-lineage specificity in transgenic mice (J.Virol 76:11024pp (2002)). Offspring from multiple independent founder animals develop follicular B-cell proliferative disorders. Thus, our lab has established the first in vivo model for KSHV LANA-dependent tumorigenesis.
Building upon our initial studies of SCID-human mouse models for primary KSHV infection (J.Exp.Med. 190:1857pp (1999)), we established a xenograft model for KSHV-associated lymphomas. Using this model, we are investigating the anti-lymphoma properties of established and novel anti-viral drugs (Cancer Res. 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.