Human Cancer Virology (VR)

Select Recent Accomplishments

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EBV Z Promoter Polymorphism/Cancer Risk

Kenney and Johannsen recently discovered that a polymorphism in the EBV promoter (Zp) controlling lytic EBV reactivation dramatically increases the amount of lytic EBV gene expression in B cells (m.s. submitted). Importantly, this EBV promoter variant (Zp-V3) is over-represented (relative to nonmalignant tissues of EBV+ patients in the same geographic regions) in both nasopharyngeal carcinomas in Hong Kong and AIDS-related lymphomas in Italy. Since this promoter polymorphism is more common in Africa and Asia than in the US, Kenney, Johannsen, and Striker will now collaborate with organ transplant physicians to determine if this Zp-V3 variant is also over-represented in post-transplant lymphoproliferative disease (PTLD) in Wisconsin relative to its frequency in normal individuals. If so, this EBV polymorphism may serve as a biomarker for transplant patients at highest risk for developing EBV-induced PTLD. In this case, this collaboration will next determine if inhibiting EBV lytic infection in transplant patients infected with Zp-V3 EBV strains reduces the risk of EBV-induced PTLD.

Human Papillomavirus, Merkel Cell Polyomavirus and their Causal Role in Cancer

Paul Lambert in lab

HPV causes over 5% of human cancers, including >95% of cervical cancers, a majority of other anogenital cancers, and ~25% of head and neck squamous cell carcinomas. Lambert has used mouse models to show that cervical cancerdevelopment and maintenance require HPV oncogenes E6 and E7, plus estrogen. Recent work in his laboratory shows that the HPV E6 oncogene contributes to maintenance of HPV genomic DNA in cells both through p53 inactivation and other functions. Additionally, Lambert and Kimple (IR) demonstrated that HPV oncogene E7 delays DNA damage repair responses, potentially explaining the clinically observed greater radiation sensitivity of HPV-positive relative to HPV-negative head and neck cancers, and providing further rationale for radiation de-escalation in treating patients with HPV-positive head and neck cancers.

EBV and KSHV genome replication and segregation studies

Genetic elements that replicate extrachromosomally are rare in mammals, but several human tumor viruses, including the papillomaviruses and gamma-herpesviruses, maintain their plasmid genomes by tethering them to cellular chromosomes. Sugden developed two complementary approaches to uncover an unprecedented clustering mechanism by which Kaposi’s Sarcoma-associated Herpesvirus (KSHV) maintains its genome extrachromosomally: Live-cell imaging and a predictive computational model revealed the formation and dynamic evolution of these clusters over multiple cell generations. This clustering, mediated by KSHV protein LANA1, controls KSHV DNA synthesis, partitioning and copy numbers and thus is central to KSHV survival and oncogenesis.