Joel Palefsky, M.D.
My group's ongoing projects fall into two main categories: 1) control of DNA tumor virus replication and clinical manifestations of DNA tumor virus infection in the setting of HIV-related immunosuppression, and 2) biology of DNA tumor virus-associated epithelial neoplasia.
Our interests are specifically in human papillomavirus (HPV) and Epstein-Barr virus (EBV). Our efforts in HPV include understanding the role of host factors in the biology of HPV infection. We have shown two proteins to be highly unregulated in both HPV-infected and EBV-infected epithelial tissues, MRP-8 and MRP-14. MRP-8 and 14 are known to be highly expressed in neutrophils, but their role in epithelial disease is not known. They also have the ability to affect ingress and egress of inflammatory cells, including monocytes. We have shown that these proteins may affect the function of the HPV 16 E7 transforming protein through inhibition of casein kinase II and inhibition of E7 phosphorylation. These proteins also affect cell cycling through modulation of other enzymes such as MAP kinase. Secreted MRPs also likely influence immune response to HPV-associated lesions, through their chemotactic properties. Using comparative genomic hybridization, RT-PCR, laser capture microscopy and microarray analysis, our laboratory is also performing studies of genetic changes in HPV-infected tissues to identify pathways of progression to invasive cancer and to identify molecular markers of progression. The laboratory has developed a gene therapy approach that uses a plasmid encoding the HSV-1 thymidine kinase (TK) gene under the control of HPV E2-response elements to drive HPV-specific expression of TK. Shown to be highly toxic and HPV-specific in vitro when the cells are exposed to acyclovir, this approach is now being tested in animal models.
Our program on EBV, like the HPV program described above, is focused on epithelial infection. We have characterized EBV gene expression in a unique EBV-associated epithelial lesion that occurs in immunocompromised patients known as hairy leukoplakia (HL). Using a cDNA library from a HL lesion generated in my laboratory, we isolated a novel cDNA clone from the BMRF-2 open reading frame. Our studies focus on mechanisms by which EBV enters epithelial cells, and we recently showed that BMRF-2 plays a role in cell attachment and entry, and this process does appear to involve cell surface integrins. Blocking of BMRF-2 binding may represent a novel approach to developing an EBV vaccine.