1. Epstein-Barr Virus At a glance Family: Herpesviridae Host: Humans Enveloped Icosahedral 120-200 nm diameter Genome: dsDNA 125-240 kbp (kilobase pairs) linear dsDNA transcription (+) mRNA genome dsDNA replication

2. Epstein-Barr Virus (EBV) Also called Human herpesvirus 4 (HHV-4) One of the most common viruses in humans Almost 90% of adults become infected with EBV Often asymptomatic Named after Michael Epstein and Yvonne BarrMichael EpsteinYvonne Barr Discovered the virus in 1964

3. Viral Infection and Replication Transmitted most commonly in saliva as well as blood The virus only infects a small number of cell types that express the receptor CR2 or CD21. These cells are pharyngeal cells lining the inner mucus membranes of the mouth and nose. Pharyngeal cells are usually the initial cells to be infected The other type of cells are the B- cells

4. Replication in Epithelial cells Permissive replication Epithelial cells permit complete lytic replication of the virus Cells allow the expression of the ZEBRA protein which activates early genes* resulting in expression of the polymerase and DNA replication. * enzymes and regulatory proteins needed to start viral replication processes.

5. Replication in B cells B lymphocytes are only semi-permissive for replication Infection is usually latent The B cells may be stimulated and transformed by the virus The cells contain a few unintegrated copies (episomes) of the virus genome These episomes are replicated every time B cell divides The latent infection may be reactivated in immunocompromised individuals as with AIDS

6. Lytic and Latent EBV infection of B cells and nasopharyngeal epithelial mucosa Epithelial cells are involved in lytic infection B cells are transformed into blasts – immature lymps A chronic virus carrier state or persistent infection is established EBV-transformed B cells are controlled by an EBV- specific cytotoxic T lymphocytes

7. Pathogenesis due to EBV EBV is responsible for the following : A. Transformation of B cells B. Burkitt's lymphoma C. Nasopharyngeal cancer (NPC) D. Oral Hairy leukoplakia E. Mononucleosis F. Hodgkin’s Lymphoma (HL)

8. Transformation of B cells Take on the appearance of “blast” or immature lymphocytes by a growth program under the regulation of EBV nuclear antigen 2 (EBNA2). EBV-infected blasts switch from the growth program to the default program by turning off EBNA2. In the absence of EBNA2, two proteins are expressed providing signals that prevent apoptosis of transformed B cells: a) Latent Membrane Protein 1 (LMP1) b) LMP2A The EBV-infected cells express little or no genetic information Are non-pathogenic Not recognized by the immune response Might be maintained as normal memory cells.

9. Burkitt's Lymphoma Tumor of the jaw and face found in children. The tumor cells show evidence of EBV genome as cccDNA ( covalently closed circular) and tumor antigens Individuals show a much higher level of anti-EBV antibodies compared to the rest of population. Tumor cells display a particular chromosomal abnormality. Burkitt's lymphoma is endemic in equatorial Africa Rarely occurs elsewhere. There may be a genetic predisposition possibly involving an association with malaria caused by Plasmodium falciparum

10. Burkitt’s Lymphoma Named after Denis Burkitt a surgeon who first described the disease in 1956 while working in equatorial AfricaDenis Burkitt surgeon Burkitt lymphoma is associated with c- myc gene translocationtranslocation a. C-myc is over expressed in a wide range of human cancers.cancers b. When mutated or over expressed, it increases cell proliferation and functions as an oncogene – gene that may cause a oncogene cell to become a cancerous

11. Distribution of Burkitt's lymphoma

12. Nasopharyngeal carcinoma (NPC) Cancer of the epithelial cells lining the nasal cavity Worldwide but most common in South East Asia, especially in southern China NPC worldwide is EBV-associated and expresses viral latent proteins Two co-factors instigated in NPC development 1. Some genetic susceptibility among southern Chinese, South East Asian and Inuit people 2. The influence of chemical carcinogens in the local diet

13. Symptoms of Nasopharyngeal Cancer A sore in the mouth that won't heal (most common symptom) or that bleeds easily Frequent nosebleeds Chronic nasal congestion, or sinus infections that do not respond to treatment Persistent sore throat Persistent hoarseness in the voice Persistent pain in the neck, throat, or ears Difficulty chewing, swallowing, or moving the jaws or tongue A lump or swelling in the neck

14. Oral Hairy Leukoplakia EBV-associated disease that results in lesions in the mouth Recently increased in as an opportunistic infection of HIV-infected patients Oral hairy leukoplakia of tongue in AIDS

15. Mononucleosis B cells are also transformed. B cells proliferate and activate suppressor CD8 T cells T cells may account for up to 80% of the white blood cells. This T cell response results in enlarged lymph glands (and enlarged liver and spleen). The activation of the T cells limits the proliferation of B cells, so that the disease resolves.

16. Symptoms of Mononucleosis Symptoms develop between 4 and 6 weeks after infection Last 2 to 4 weeks Swollen lymph nodes Extreme tiredness Fever Sore muscles Sore throat Up to 50 percent of people swollen spleen, and some will have an enlarged liver. Loss of appetite, Rarely jaundice

17. Hodgkin’s Lymphoma Also known as Hodgkin's disease, First described by Thomas Hodgkin in 1832.Thomas Hodgkin Occurs in young adulthood (age 15–35) Individuals over 55 years old Characterized by the presence of Reed-Sternberg cells.Reed-Sternberg cells In approximately 50% of cases, the Reed-Sternberg cells are infected by the Epstein-Barr virus.Epstein-Barrvirus Hodgkin's lymphoma was one of the first cancers to be cured by radiationcancers Cure rate is about 93%, making it one of the most curable forms of cancer. cure rate is about 93%, making it one of the most curable forms of cancer. cure rate is about 93%, making it one of the most curable forms of cancer.

18. Symptoms of Hodgkin’s Lymphoma Swollen, painless, and rubbery lymph nodes are the most common signlymph nodes Splenomegaly: occurs in about 30% of people with Hodgkin's lymphomaSplenomegaly Hepatomegaly: due to liver involvement in the disease in about 5% of casesHepatomegaly Systemic symptoms in 1/3 of patients * Low-grade fever * night sweats * 10% weight loss * Itchy skin (pruritus)pruritus * Fatigue.Fatigue

20. References Rickinson, A.B. and E. Kieff, Epstein-Barr virus in Fields Virology. ed., ed. D. Knipe and P. Howley. Vol. 2001, Philadelphia: Lippincott Williams and Wilkins. Young, L.S. and A.B. Rickinson, Epstein-Barr virus: 40 years on. Nat Rev Cancer, 2004. 4(10): p. 757-68.PubMedPubMed http://www.seedwiki.com/wiki/lisas_epstein-barr_virus http://www.bio.davidson.edu/courses/Immunology/Students/spring2006/Ma gargal/mononucleosis.htm The Department of Pathology and Microbiology The teaching and research activities of the Department of Pathology and Micro Wikipedia