Thesis (Ph. D.)--University of Hong Kong, 2008. / Also available online.

Thesis (M. Phil.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 93-117).

Thesis (M. Phil.)--University of Hong Kong, 1995. / Includes bibliographical references (leaf 155-198).

Thesis (M. Phil.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 114-136).

Tübingen, Univ., Diss., 2005.

Thesis (M.Med.Sc.)--University of Hong Kong, 2003. / Includes bibliographical references (leaves 40-47). Also available in print.

Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), occurring in isolated attacks or progressive forms. Many observations implicate Epstein-Barr virus (EBV) in the pathogenesis of MS. With the relentless accumulation of evidence for a significant pathogenic role of EBV in MS, I believe it may be possible to prevent and cure MS by effectively controlling EBV infection. Currently, monoclonal antibodies (MAb) are used as therapeutics for a molecular targeted approach to slowing disease progression in MS. However, to my knowledge, there have been no antibodies targeted against EBV infection in any model of MS. The objective of this study is to determine whether or not a MAb against EBV could be a therapeutic target for EAE. In this study, I will propose an experiment that will examine the effects of intraperitoneal injection of MAb F-2-1 in 2-month-old new humanized BALB/c Rag2-/- ll2rg-/- (BRG) adult EBV/EAE male mice. My expected results suggest that mice with EBV/EAE + MAb F-2-1 may have an attenuated clinical disease course. Through immunohistochemical studies, I will also propose that MAb F-2-1 may decrease inflammation, demyelination and axonal loss in the CNS of mice with EAE. I believe that this novel treatments success would depend on MAb F-2-1’s ability to inhibit clonal expansion of EBV-infected autoreactive B cell in the CNS. Ultimately, my proposed experiment suggests that inhibition of virus-cell fusion of EBV to the B cell membrane might attenuate neuropathology in EAE. I hope that my prospective study highlights the importance of controlling EBV in patients with MS and provides grounds for optimism on how to successfully treat MS by controlling EBV infection. In conclusion, by proposing an alternative therapeutic approach, I hope that this hypothetical experiment will aid in future investigations that could further our knowledge on treatment and prevention of multiple sclerosis

Epstein-Barr Virus (EBV) is well known to manipulate the host ubiquitin machinery to facilitate its latent persistence and oncogenesis, exemplified by LMP1 signal transduction that activates multiple transcription factors, including NFκB, AP1, and IRF7/IRF4, which promote cell survival and outgrowth, and control immune response and inflammation. It is therefore vital to delineate the detailed mechanisms underlying LMP1 signal transduction for understanding EBV-mediated oncogenesis. p62 (also called SQSTM1, Sequestosome 1) is a ubiquitin sensor and a signal transducing adaptor that interacts with TRAF6 and facilitates the recruitment of ubiquitinated signal intermediators for the activation of NFκB and AP1 in diverse contexts. In turn, p62 is induced by NFκB. However, the interaction between p62 and EBV latency has never been studied. We have recently published interesting and important results, which imply a crucial role for p62 in EBV-mediated oxidative stress. In this study, we further show that p62 is upregulated in EBV latency, with the contribution of LMP1-mediated NFκB and AP1 activities. In turn, p62 participates in LMP1 signal transduction through its interaction with TRAF6, promoting TRAF6 ubiquitination. shRNA-mediated p62 depletion downregulates LMP1-TRAF6 interaction and TRAF6 ubiquitination, and significantly impairs AP1 activity; however, with no detectable effects on NFκB activity. These observations imply that TRAF6-p62 interaction differentiates LMP1 signaling to NFκB and AP1 activation. As a consequence, p62 depletion promotes etoposide-induced apoptosis. These findings identify p62 as a novel player in EBV LMP1 signaling to AP1 activation that is crucial for LMP1-mediated ROS production.

Purification of Epstein-Barr virus-associated deoxyribonuclease (EBV-DNase) from Raji and P3HR-1 cells treated with 12-0-tetradecanoylphorbol-13-acetate and sodium butyrate was performed by sequential ion-exchange column chromatography and fast protein liquid chromatography. The enzyme activity, protein concentration, yield, specific activity, purification profiles, and polypeptide patterns by electrophoretic analysis in each column purification step were determined. The characteristics of the partially isolated EBV-DNase were demonstrated by the enzyme activity, DNA binding affinity, and inhibition by the nasopharyngeal carcinoma patient sera and rabbit polyclonal antibodies against the partially purified EBV-DNase. A nonisotopic assay was developed as a new method in detecting the nuclease. EBV-DNase was purified to homogeneity by FPLC. The molecular weight of the EBV-DNase was 58 KDa as determined by sodium dodecylsulfate polyacrylamide gel electrophoresis, immunostaining, and radioimmunoprecipitation using nasopharyngeal carcinoma patient sera and rabbit polyclonal antibodies.