Office 248 / Lab 256
PA Biotechnology Center
3805 Old Easton Road
Doylestown, PA 18902
TEL: 215-489-4906
FAX: 215-489-4920
Xuanyong.Lu@drexelmed.edu
Ph.D. 1989, Goettingen University, Goettingen, Germany
Keywords:
Hepatitis B virus, HBV entry, viral attachment, fusion, protease, apoptosis, serine protease inhibitor, apoptosis inhibitor, cancer, virology.
Research Interests:
My researches focus on the study of hepatitis B virus (HBV), a major human pathogen responsible for acute and chronic liver disease. Estaminately, more than 350 million people are chronically infected with HBV worldwise and one third of these individuals will turn out to be serious liver diseases such as liver cirrhosis, chronic liver failure, and hepatocellular carcinoma (HCC) that result in an estimated 1 million deaths annually. Therefore, there is a clear need for understanding HBV infection and introduction of safe and effective therapies for chronic hepatitis B virus.
 A major limitation to thoroughly studying HBV and exploration of new anti-HBV drugs has been the lack of suitable cell-lines that are susceptible to HBV infection. Human hepatocyte primary cultures, while susceptible to HBV infection, are viable only for a very limited amount of time following the explants. Alternatively, hepatoma cell lines such as HepG2, which are capable of supporting viral replication and producing progeny viruses, generally do not allow the infection of serum derived HBV to happen. Therefore, our first effort is to establish a cell line that is permissible to HBV infection.
We have previously reported that, limited digestion of human and woodchuck hepatitis viruses with the Staphylococcal protease V8 rendered the viruses “infectious” in cultured HepG2 cells. The infected HepG2 cells were shown to produce progeny viruses. The reason that V8 protease treatment induces viral infectivity is not clear. Our studies suggest that the proteolysis of V8 has exposed a region that contains a hydrophobic motif associated with membrane fusion that probably results in virus-cell membrane fusion, permitting viral genome entry into the cytosol, and then triggering HBV infection. The fusogenesis of this motif was supported by the fact that synthetic peptides corresponding to this motif induced fusion of bio-membranes, and of HepG2 cells from without in vitro (our unpublished observations). Other evidence supports this assumption comes from that similar motif with the identical sequence has been found in the other viral envelope polypeptides associated with fusion, including Human Immunodeficiency Virus (HIV) and influenza virus. Accordingly, the resistance of HepG2 cells to HBV infection is a possible result of the lack of a proteolysis that induces virus-cell fusion. The observation that supports this hypothesis is the finding of the over-expressing of a kind of protease inhibitor named serine protease inhibitor (SPI) in HepG2 cells. The probable mechanism is that the SPI by inactivating vital proteases in the virus-cell fusion process prevents infecting and gives immunity to the HepG2 cells. Further support for this hypothesis is provided when an anti-sense oligo was used to down regulate the SPIK gene expression led to a potential HBV infection of HepG2 cells in vitro. Logically following this, a permanent cell line that can be infected by HBV could be established by silencing the over-expressed SPI in the HepG2 cell line. Those studies are carrying on in our laboratory now.
 The Second field, in which I am interested, is controlling cancer growth by silence of over-expressed apoptosis inhibitors in cancer cells. Cancer is a complex disease involving a myriad of molecular and cellular processes. The gradual accumulation of genetic changes that leads to the development of the cancer recently was found closely linking with the cell apoptosis. Dysregulation of apoptosis has resulted in carcinogenesis, tumor progression, even in the resistance of tumor cells to radio-and chemotherapy. The relevant anti-apoptosis mechanism of cancer cells is thought to inactivate the crucial protease involving in the cell apoptosis by over-expression of a kind of regulation protein named apoptosis inhibitor (IAP) and serine protease inhibitor (SPI). Recently our studies suggest that the apoptosis inhibitors such as cIAP1and cIAP2 and serine protease inhibitor (SPI, see above) were over-expressed in hepatoma cell lines as well as in liver cancer cells. The up-regulation of the IAPs and SPI has also been identified in the other cancers such as breast cancer, lung cancer, pancreatic cancer and prostate cancer. Those findings support the hypothesis that the over-expression of apoptosis inhibitor triggers the cell carcinogenesis. If it were true, down regulation of over-expressed apoptosis inhibitor, consequently reinstating the apoptosis of cancer cell, probably could be used to control the cancer development. This new strategy to cancer therapy is developing in our laboratory now.
Publications
- Xuanyong Lu, Paul Weiss and Timothy Block. A phage with high affinity for hepatitis B surface antigen for detection of HBsAg. The Journal of Virological Methods. 2004. 119 (1): 51-54
- Xuanyong Lu and Block T. Study of the early steps of the Hepatitis B Virus life cycle. Int. J. Med. Sci. 2004, 1(1): 21-33
- Xuanyong Lu, Trang Tran, Ender Semick and Timothy Block. 2003 (Nov). The alkylated imino sugar, n- (n-nonyl)-deoxygalactonojirimycin, reduces the amount of hepatitis B virus (HBV) nucleocapsid in tissue culture. J. Virol. 77 (22), 11933-11940.
- Pamela Norton, Gong Q. Mehta A, Lu X and Block T. 2003. Hepatitis B Virus-mediated changes of apolipaprotein mRNA abundance in cultured hepatoma cells. J. Virol 77(9) 5503-5506.
- Mehta A, Ouzounov S, Jordan R, Simsek E, Lu X, Moriarty RM, Jacob G, Dwek RA, Block TM. 2002. Imino sugars that are less toxic but more potent as antivirals, in vitro, compared with N-n-nonyl DNJ. Antivir Chem Chemother. Sep; 13(5): 299-304.
- Xuanyong Lu, Tawfiq Hazboun and Timothy Block. 2001, Limited proteolysis induces woodchuck hepatitis virus infectivity for human HepG2 cells. Virus Research. 73(1): 27-40.
- Xuanyong Lu, Yefei Lu, Ryan Geschwindt, Raymond A. Dwek & Timothy M. Block. 2001. The hepatitis B virus MHBs antigen is selectively sensitive to glucosidase mediated processing in the endoplasmic reticulum. DNA and Cell biology, 20(10), 647-656.
- Mehta A. Lu X. Block T. Willis A. Dwek R. Tennant B. Blumberg B. 2001 Synovial stimulatory protein fragments copurify with woodchuck hepatitis virus: implications for the etiology of arthritis in chronic hepatitis B virus infection. Arthritis & Rheumatism. 44(2):486-7.
- Timothy Block, Xuanyong Lu, Anand Mehta, Brauch S. Blumburg, Bud Tennant, Mathew Ebling, Brent korba, David Lansky, Gray S. Jacob, and Raymond Dwek. 1998, Treatment of Hepatitis virus in chronically infected woodchucks with folding and trafficking inhibitor. Nature medicine. Vol. 4, No. 5, 610-614.
- Block TM. Lu X. Mehta A. Park J. Blumberg BS. Dwek R. 1998, Role of glycan processing in hepatitis B virus envelope protein trafficking. Advances in Experimental Medicine & Biology. 435:207-16.
- Lu Xuanyong, Anand Metha, Dadmarz M. Dwek .R. Blumberg .B. and T. Block. 1997 Aberrant trafficking of hepatitis b virus glycoproteins in which N-glycan processing is inhibited. PNAS USA 94 2380-2385.
- Lu Xuanyong, Block T., Gerlich W. H.. 1996 Protease-induced infectivity of hepatitis B virus for a human hepatoma cell line. J. Viriol. 70, 2277-2285.
- Lu Xuanyong, Anand Metha, Raymond Dwek, Terry Butters and Timothy Block. 1995 Evidence the N-linked glycosylation is necessary for hepatitis B virus secretion. Virology. 213. 660-665.
- Block T., Lu Xuanyong, Frances M. Platt, Graham R. Foster, Wolfram H. Gerlich, Baruch S. Blumberg and Raymond A. Dwek.1994 The secretion of human hepatitis B virus is inhibited by the imino sugar, N-butyldeoxynojirimycin. PNSA, USA 91. 2235-2239 1994.
- Bruss V., Lu Xuanyong., Thomssen R., Gerlich W. H., 1994 Posttranslational alterations in transmenbrance topology of the hepatitis B virus large envelope protein. EMBO J., 13. 2273-2279.
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