Epstein-Barr virus in human disease
Infection with Epstein-Barr virus (EBV), a lymphotropic human herpesvirus (HHV-4), is highly prevalent worldwide (Everybody's virus) in all populations. EBV is the direct causative agent of Infectious Mononucleosis (IM or Pfeiffer's Disease) and has been related to a spectrum of malignancies and chronic diseases.
EBV, being a herpesvirus, has two distinct life cycles, the latent and lytic phase. During lytic phase, EBV produces new viral particles which infect new cells. EBV produces many immunogenic proteins during the lytic phase, which are recognized by the immune system. To prevent clearing by the immune system, EBV has developed a strategy to minimize antigen exposure to the immune system when EBV is not producing new viral particles. EBV minimizes expression of proteins during this latent phase, which minimizes EBV antigen exposure to the immune system.
Infectious mononucleosis (IM)
IM can be considered the clinically manifest form of a primary EBV infection, in which the the paracortex of lymphoid tissues expand by the proliferation of EBV-infected polyclonal B blasts. A small number of these EBV-positive cells will express lytic cycle antigens, which trigger a immune respons of the activated T cells that accompany the growth of the B blasts. The strong response of the immune system against this primary viral infection is responsible for the fatigue symptons seen in IM.
Malignancies
EBV was first identified in Burkitt Lymphoma (BL), a B cell lymphoma that was originally described in equatorial Africa (the malaria belt) where it accounts for approximately 50% of all childhood cancers. EBV is present in 95% of these endemic BL, however, in Europe and the USA the association is only 10-20%. This difference has been ascribed to the early age of EBV infection in Africa compared to industrialized countries.
Hodgkin's Disease (HD) is characterized by mononuclear Hodgkin cells and their multinucleated variant, the Reed-Sternberg cells, which in many cases of HD are derived from B cells. In industrialized countries, EBV is associated with 40-60% of HD cases, but depending on race and socio-economic status of the population, this percentage may approach 100% as found in some developing countries. There is clear evidence that risk for HD occuring from early childhood through middle age is associated with factors in the childhood environment that influence the age at which EBV infection takes place (i.e. social class, population density, geographic region). Furthermore, it has been shown that people who have had IM have a threefold higher risk for getting HD. It has been suggested that EBV is an important cofactor in the pathogenesis of HD, but that in patients with relatively intact immune systems, EBV-positive neoplastic cells are eradicated and only cells capable of virus-independent growth survive.
EBV-related lymphomas can also develop in immunocompromized patients. In organ transplant patients who are being treated with immunosuppressive drugs, posttransplant lymphoproliferative disorders (PTLDs) are a feared complication. Most PTLDs occur in patients who are EBV seronegative prior to the transplantation and who, because of the immunosupressive druges, are unable to timely mount an effective immune response against the primary infection introduced with the transplanted organ. In AIDS patients, AIDS-related lymphomas can develop which are mostly of B cell origin and contain the patient's intrinsic EBV.
Although EBV is described as being lymphotropic, EBV has also been shown to be involved in several malignancies of epithelial origin. Undifferentiated Nasopharyngeal carcinoma, which arises from the fossa of Rosenmuller and Eustachian cushions or in the roof of the nasopharynx, has an EBV-association up to 100%. NPC shows a characteristic racial and geographical distribution with the highest incidence among males in Southern China and natives of the Arctic region. Distibution and migration studies have proposed numerous factors to play a role in the genesis of NPC, such as consumption of Cantonese-style preserved foods, exposure to smoke and alcohol, use of Chinese herbal drugs and nasal oil and hereditary factors, such as HLA type. Clonal EBV-infection has been shown in premalignant lesions of the nasopharynx, suggesting involvement of EBV prior to the carcinomatous state.
The worldwide incidence of EBV-positive tumors in regular gastric adenocarcinomas is 10%, and up to 30% in gastric stump carcinomas. The viral genomes in these EBV-associated tumors have been shown to be monoclonal.
Besides such malignancies, EBV has been associated with chronic autoimmune diseases such as Multiple Sclerosis (M.S.), Systemic Lupus Erythematosus (S.L.E.) and Rheumatoid Arthritis (R.A.).
Our research
The pathogenesis and molecular details of virus-host interactions in most of these diseases are still poorly understood and intervention is mainly non-specific (chemo-radiotherapy). It is our goal to unravel the pathogenic role(s) of EBV and to improve early diagnosis and design novel intervention strategies of EBV-related diseases, through intense clinical-laboratory collaboration and study of defined patient materials besides in vitro cq. in vivo model systems of human disease.
Projects include design and evaluation of new molecular diagnostic methods, deciphering molecular pathogenic mechanisms for EBV-driven (tumor) cell growth and immune escape, design of novel approaches in EBV-specific tumor immunotherapy and novel anti-viral chemotherapies, as well as basic cell-biology studies on function and behaviour of viral proteins and miRNAs with the cells and cellular vesicles, such as exosomes. For these projects we have unique EBV reagents and molecular expertise and are supported by several KWF and EU funded grants. We actively participate in postgraduate trainings and teaching programs at VUmc and use our experimental expertise for clinical support in patient diagnosis and monitoring nation-wide. We have a large network of national and international collaborations, with a special aim to improve health care in developing countries.
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