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.
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Palefsky JM, Minkoff H, Kalish LA, Levine A, Sacks HS, Garcia P, Young M, Melnick S, Miotti P, Burk R (1999). Cervicovaginal human papillomavirus infection in HIV-positive and high-risk HIV-negative women. J Natl Cancer Inst 91:226-235.
Lagenaur L, Palefsky JM (1999). Regulation of EBV promoters in oral epithelial cells and lymphocytes, J Virol 73: 6566-6572.
Holly EA, Ralston ML, Darragh TM, Greenblatt RM, Jay N, Palefsky JM (2001). Prevalence and risk factors for anal squamous intraepithelial lesions in women. J Natl Cancer Inst 93:843-9.
Haga T, Sun-Hun Kim S-H, Jensen RH, Darragh T, Palefsky JM. (2001) Detection of genetic changes in anal intraepithelial neoplasia (AIN) of human immunodeficiency virus (HIV)-positive and HIV-negative men. J Acq Immune Defic Syndr, 26:256-262.
Palefsky JM, Berline J, Greenspan D, Greenspan JS. (2001). Evidence for trafficking of Epstein-Barr virus strains between hairy leukoplakia and peripheral blood lymphocytes. J Gen Virol, 83: 317-21.
Sethi N, Palefsky JM (2003). Treatment of human papillomavirus (HPV) type 16-infected cells using herpes simplex virus type 1 thymidine kinase-mediated gene therapy transcriptionally
regulated by the HPV E2 protein. Hum Gene Ther. 14: 45-57.
Tugizov SM, Berline JW, Palefsky JM (2003). Epstein-Barr virus infection of polarized tongue and nasopharyngeal epithelial cells. Nat Med 9:307-14.
Sethi N, Palefsky JM (2004). Transcriptional profiling of dysplastic lesions in K14-HPV16 transgenic mice using laser microdissection. FASEB J 190:1241-8.
Sharof Tugizov S, Berline J, Herrera R, Penaranda M-E, Nakagawa M, Palefsky JM. Inhibition of HPV16 E7 phosphorylation by the S100 MRP-8/14 protein complex J Virol, 2004, in press
information last updated September 2004
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Biomedical Sciences (BMS) Graduate Program
