Epstein-Barr Virus Causes Lymphomas

EBV has been declared a Class I human carcinogen by the IARC. (Epstein Barr Virus and Kaposi's Sarcoma Herpesvirus/Human Herpesvirus 8. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans). IARC Monograph 70. Lyon: International Agency for Research on Cancer; 1997.)

"5.5 Evaluation. There is sufficient evidence for the carcinogenicity of EBV in the causation of Burkitt's lymphoma, sinonasal angiocentric T-cell lymphoma, immunosuppression-related lymphoma, Hodgkin's disease and nasopharyngeal carcinoma."

"EBV is carcinogenic to humans (Group I)."

Review

Epstein-Barr virus, infectious mononucleosis, Burkitt's lymphoma and nasopharyngeal carcinoma. G Klein. Israel J Med Sci 1977 Jul;13(7):716-724. "The timing and extent of seroconversion are strongly related to socioeconomic status. In low socioeconomic groups, infection occurs during early childhood, as a rule. It is not accompanied by any recognized disease, and the route of transmission is unknown. Only a minority of children become infected in high socioeconomic groups where a later infection, during the teens, predominates."

The spectrum of Epstein-Barr virus-associated lymphoproliferative disease in Korea: incidence of disease entities by age groups. EY Cho, KH Kim, WS Kim, KH Yoo, HH Koo, YH Ko. J Korean Med Sci 2008 Apr;23(2):185-192. "T or NK cell NHLs were the most common forms of EBV-positive NHLs (107/167, 64%); among these, nasal-type NK/T cell lymphomas were the most common (89/107, 83%). According to the age, Burkitt's lymphoma was the most common in early childhood; in teenagers, chronic (active) EBV infection-associated LPD was the most common type. The incidence of NK/T cell lymphoma began to increase from the twenties and formed the major type of EBV-associated tumor throughout life. Diffuse large B cell lymphoma formed the major type in the sixties and seventies."

EBV and Hodgkin's Disease

Epstein-Barr virus and Hodgkin's disease. H Herbst, G Niedobitek. Int J Clin Lab Res 1993;23(1):13-16. "Seroepidemiological and molecular biological studies have established an association of Hodgkin's disease with Epstein-Barr virus. Recently, Epstein-Barr virus genomes and gene products have been detected in the neoplastic cells of approximately 50% of cases, most notably the latent membrane protein, which has transforming potential."

Risk factors for Hodgkin's disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents. FE Alexander, RF Jarrett, D Lawrence, AA Armstrong, J Freeland, DA Gokhale, E Kane, GM Taylor, DH Wright, RA Cartwright. Br J Cancer 2000 Mar;82(5):1117-1121. 19/103 tumors were EBV+. History of infectious mononucleosis & Hodgkin's disease, OR= 2.43 (95% CI= 1.10-5.33); history of IM and EBV-positive HD, OR= 9.16 (95% CI= 1.07-78.31).

The correlation of Epstein-Barr virus expression and lymphocyte subsets with the clinical presentation of nodular sclerosing Hodgkin disease. A Kandil, S Bazarbashi, WA Mourad. Cancer 2001 Jun 1;91(11):1957-1963. EBV expression was seen in 24 (50%) cases.

South Asian ethnicity and material deprivation increase the risk of Epstein-Barr virus infection in childhood Hodgkin's disease. KJ Flavell, JP Biddulph, JE Powell, SE Parkes, D Redfern, M Weinreb, P Nelson, JR Mann, LS Young, PG Murray. Br J Cancer 2001 Aug;85(3):350-356. "62% of [55] cases were Epstein-Barr virus-positive... The relative risk of Epstein-Barr virus-positivity showed a gradient with increasing Townsend score; the risk being 7-times higher in the most deprived quartile compared with the least deprived group."

Epstein-Barr virus (EBV) in Chinese pediatric Hodgkin disease: Hodgkin disease in young children is an EBV-related lymphoma. XG Zhou, K Sandvej, PJ Li, XL Ji, QH Yan, XP Zhang, JP Da, SJ Hamilton-Dutoit. Cancer 2001 Sep 15;92(6):1621-1631. In 104 pediatric and 52 adult Chinese HD cases, "EBV was identified in tumor cells in 113 of 156 (72%) HD cases but was more frequent in pediatric cases (93 of 104; 89%) compared with adult cases (20 of 52; 38%) (P < 0.01; chi-square test). EBV was found in 86 out of 91 (95%) cases in children aged 3-10 years and in 7 out of 13 (54%) cases in children aged 11-14 years (P < 0.01; chi-square test).... The authors believe that pediatric HD now should be regarded as a distinctive EBV-related lymphoma."

A defective, rearranged Epstein-Barr virus genome in EBER-negative and EBER-positive Hodgkin's disease. YJ Gan, BI Razzouk, T Su, JW Sixbey. Am J Pathol 2002 Mar;160(3):781-786. "The Epstein-Barr virus (EBV) has been linked to approximately half the cases of Hodgkin’s disease (HD), with virus localized by EBER in situ hybridization to the malignant Reed-Sternberg cell that characteristically makes up less than 1% of the tumor mass. Recent descriptions of relapsed HD, shown to be EBV-positive at initial diagnosis but EBV-negative on reoccurrence, raise the possibility of viral DNA loss during tumor progression in some individuals." 8/24 EBER-negative HD had PCR evidence of defective EBV DNA. "Detection of defective EBV genomes with the potential to disrupt viral gene regulation suggests one mechanism for pathogenic diversity that may also account for loss of prototypic EBV from individual tumor cells."

Epstein-Barr virus in Hodgkin's disease: the example of central Tunisia. S Korbi, M Trimeche, B Sriha, MT Yacoubi, S Hmissa, M Mokni, P Delvenne, J Boniver, S Rammeh. Ann Pathol 2002 Apr;22(2):96-101. EBV early RNA transcripts (EBER) was detected in 70% of 77 cases.

Hematopoietic and lymphatic cancers in relatives of patients with infectious mononucleosis. H Hjalgrim, K Rostgaard, J Askling, M Madsen, HH Storm, CS Rabkin, M Melbye. J Natl Cancer Inst 2002 May 1;94(9):678-681. "The unremarkable risk for Hodgkin's lymphoma in family members of patients with EBV-related infectious mononucleosis indicates that socioeconomic confounding is an unlikely explanation for the association between EBV-related infectious mononucleosis and Hodgkin's lymphoma."

Epstein-barr virus-associated non-Hodgkin's lymphoma of B-cell origin, Hodgkin's disease, acute leukemia, and systemic lupus erythematosus: a serologic and molecular analysis. W Mitarnun, J Pradutkanchana, S Takao, V Saechan, S Suwiwat, T Ishida. J Med Assoc Thai. 2002 May;85(5):552-9. In 58 patients, "EBV internal repeat-1 region (IR-1) in peripheral blood CD3+ cells was detected in 10 of 14 patients (71.5%) with NHL-B, 3 of 8 patients (37.5%) with Hodgkin's disease, 1 of 6 patients (16.7%) with acute leukemia, 4 of 9 patients (44.5%) with SLE, and was not detected in any of the 21 patients with other diseases."

Hodgkin disease in adult and juvenile groups from two different geographic regions in Brazil: characterization of clinicopathologic aspects and relationship with Epstein-Barr virus infection. E De Oliveira, MM Bacchi, ES Abreu, L Niero-Melo, CE Bacchi. Am J Clin Pathol 2002 Jul;118(1):25-30. "HD in Brazilian patients is highly associated with EBV infection."

Heterogeneity of risk factors and antibody profiles in epstein-barr virus genome-positive and -negative hodgkin lymphoma.
ET Chang, T Zheng, ET Lennette, EG Weir, M Borowitz, RB Mann, D Spiegelman, NE Mueller. J Infect Dis 2004 Jun 15;189(12):2271-2281. "EBV-positive patients were less educated and more likely to have smoked cigarettes and had more prevalent and higher EBV antibody titers, compared with EBV-negative patients."

Phenotype and frequency of Epstein-Barr virus-infected cells in pretreatment blood samples from patients with Hodgkin lymphoma. G Khan, A Lake, L Shield, J Freeland, L Andrew, FE Alexander, R Jackson, PR Taylor, EA McCruden, RF Jarrett. Br J Haematol 2005 May;129(4):511-519. "[T]he frequency of circulating EBV-infected cells was significantly higher (P < 0.001) in pretreatment blood samples from EBV-associated cases when compared with non-EBV-associated cases."

HLA-A*02 is associated with a reduced risk and HLA-A*01 with an increased risk of developing EBV+ Hodgkin lymphoma. M Niens, RF Jarrett, B Hepkema, IM Nolte, A Diepstra, M Platteel, N Kouprie, CP Delury, A Gallagher, L Visser, S Poppema, GJ te Meerman, A van den Berg. Blood 2007 Nov 1;110(9):3310-3315. 70 patients with EBV+ HL, 31 patients with EBV- HL, and 59 control participants. "HLA-A*01 was significantly overrepresented and HLA-A*02 was significantly underrepresented in patients with EBV+ HL versus controls and patients with EBV- HL. In addition, HLA-A*02 status was determined by immunohistochemistry or HLA-A*02-specific polymerase chain reaction (PCR) on 152 patients with EBV+ HL and 322 patients with EBV- HL. The percentage of HLA-A*02+ patients in the EBV+ HL group (35.5%) was significantly lower than in 6107 general control participants (53.0%) and the EBV- HL group (50.9%)."

Expression of Epstein-Barr virus in Hodgkin lymphoma in a population of United Arab Emirates nationals. S Al-Salam, A John, S Daoud, SM Chong, A Castella. Leuk Lymphoma 2008 Jul 25:1-9. "Nodular sclerosis (NS) subtype was the most common type of HL among UAE nationals followed by mixed cellularity (MC), lymphocytic predominant (LP), unclassified, lymphocytic depletion (LD) and lymphocyte rich (LR) subtypes, respectively. EBV was seen in 17 of 45 (38%) cases of HL and was predominately seen in the MC subtype followed by NS, LD and LR subtypes, respectively. EBV was more frequently expressed in HL in the pediatric age group than the adult age group."

Example: Anti-smoking junk

Cigarette smoking and risk of Hodgkin's Disease: A population-based case-control study. NC Briggs, HI Hall, EA Brann, CJ Moriarty, RS Levine. Am J Epidemiol 2002;156(11):1011-1020. "Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals adjusted for age, registry, race/ethnicity, Jewish upbringing, education, and childhood domicile. Compared with never smokers, current smokers had a significantly increased risk of Hodgkin’s disease (odds ratio (OR) = 1.8, 95% confidence interval (CI): 1.3, 2.9)." They simply ignored EBV infection! This is an example of deliberate anti-smoker scientific fraud, under the auspices of the Centers for Disease Control, and published by the coruupt Johns Hopkins Bloomberg School of Public Health. In the year 2002, when no one can legitimately pretend ignorance, they purposely ignore the role of EBV infection, in order to falsely blame by confounding.

See the National Cancer Institute fudge about EBV and HD!

The National Cancer Institute claims that "At this time, the cause or causes of Hodgkin's disease are not known," and insists on calling EBV merely a "risk factor:" "Viruses -- Epstein-Barr virus is an infectious agent that may be associated with an increased chance of getting Hodgkin's disease." They refuse to admit that EBV is CAUSAL, and not merely associated with an increased chance of getting Hodgkin disease. (Risk Factors Associated with Hodgkin's Disease. National Cancer Institute. Posted 06/25/1999, Updated 09/16/2002; viewed 11-30-02, 06-18-05, 10-02-05, and 07-01-06.)

See the American Cancer Society drag its feet about EBV and HD!

The American Cancer Society mirrors the attitude of the NCI in its evasion of the causal role of EBV. "There seems to be a slightly increased rate for Hodgkin's disease in people who have had infectious mononucleosis (sometimes called "mono" for short), an infection caused by the Epstein-Barr virus. However, half of patients with Hodgkin's disease show no evidence of a previous Epstein-Barr virus infection." And they insist that "Even if someone has one or more risk factors for Hodgkin's disease, it is impossible to know for sure how much that risk factor could contribute to causing the cancer. In general, we can say that no major risk factors for Hodgkin's disease have been discovered yet." (What Are the Risk Factors for Hodgkin's Disease? American Cancer Society, as of 10-02-05 and 07-01-06.)

EBV and Burkitt lymphoma

Precipitating antibody in human serum to an antigen present in cultured Burkitt's lymphoma cells. LJ Old, EA Boyse, HF Oettgen, ED Harven, G Geering, B Williamson, P Clifford. Proc Natl Acad Sci U S A 1966 Dec;56(6):1699-1704. 19 of 20 (95%) sera of patients with carcinoma of the postnasal space were positive to an antigen prepared from cultured Burkitt's lymphoma cells.

A Burkitt lymphoma cell line with integrated Epstein-Barr virus at a stable chromosome modification site. NC Popescu, MC Chen, S Simpson, S Solinas, JA DiPaolo. Virology 1993 Jul;195(1):248-251. "Virus insertion into chromosomal DNA caused a stable modification site expressed as a distinctive achromatic region adjacent to the band 2p13. The chromatid lesion at the site of EBV integration involving a recombinogenic and fragile site may have contributed to the development of the NAB-2 BL."

The role of Epstein-Barr virus-encoded small RNAs (EBERs) in oncogenesis. A Nanbo, K Takada. Rev Med Virol 2002 Sep-Oct;12(5):321-326. "EBERs play a key role in the maintenance of malignant phenotypes of Burkitt's lymphoma (BL) cells... Furthermore, we demonstrated that EBERs confer resistance to interferon (IFN)-alpha-induced apoptosis by inhibition of double-stranded (ds) RNA-activated protein kinase (PKR), which is the key mediator of the antiviral effect of IFN-alpha. These studies provide a new notion that RNA molecules contribute to oncogenesis."

Frequent presence of subtype A virus in Epstein-Barr virus-associated malignancies. SC Peh, LH Kim, S Poppema. Pathology 2002 Oct;34(5):446-450. In 17 Hodgkin's, 14 Burkitt's, 4 T-cell and 3 B-cell non-Hodgkin's lymphomas, "All cases showed presence of type A virus, consistently detected with nested PCR protocol but not with single step PCR. There was no type B virus or mix infections detected."

Sporadic paediatric and adult Burkitt lymphomas share similar phenotypic and genotypic features. SS Chuang, WT Huang, PP Hsieh, YC Jung, H Ye, MQ Du, CL Lu, CY Cho, SC Hsiao, YH Hsu, KJ Lin. Histopathology 2008 Mar;52(4):427-435. In 17 paediatric and 14 adult BLs, 24% versus 21% were positive for EBER.

Detection of Epstein-Barr virus in children and adolescents with Burkitt's lymphoma by in situ hybridization using tissue microarrays. M Pizza, P Bruniera, SM Luporini, HR Marcelino da Silva, ML Borsato, HC de Castro, FA Soares, RA Paes. Hematology 2008 Apr;13(2):114-118. "The presence of EBV using in situ hybridization was found in 33/50 (66%) and there was no association between the presence of the virus in the tumor cells or patient age, as well as the survival rate."

Viral Studies in Burkitt Lymphoma: Association With Epstein-Barr Virus but Not HHV-8. EM Queiroga, G Gualco, L Chioato, WJ Harrington, I Araujo, LM Weiss, CE Bacchi. Am J Clin Pathol 2008 Aug;130(2):186-192. "EBV was present in 45.0% of all BL cases with higher incidence in the pediatric group; most cases were EBV type A. We found no association of BL with HHV-8 in EBV + BL or in EBV-cases, including the HIV + BL group." Number of cases is not given in the abstract.

EBV & Other Lymphomas

[Detection of Epstein-Barr virus nucleic acid sequences in non-Hodgkin's lymphoma]. A Sauerbrei, P Wutzler, I Farber, K Wutke, B Brichacek, I Hirsch. Arch Geschwulstforsch 1987;57(6):445-452. EBV nucleic acid and EBNA were found in 5/25 NHLs.

Epstein-Barr virus-associated peripheral T-cell lymphoma of activated CD8 phenotype. IJ Su, KH Lin, CJ Chen, HF Tien, HC Hsieh, DT Lin, JY Chen. Cancer 1990 Dec 15;66(12):2557-2562. Two childhood cases.

Frequent latent Epstein-Barr virus infection of neoplastic T cells and bystander B cells in human immunodeficiency virus-negative European peripheral pleomorphic T-cell lymphomas. P Korbjuhn, I Anagnostopoulos, M Hummel, M Tiemann, F Dallenbach, MR Parwaresch, H Stein. Blood 1993 Jul 1;82(1):217-223. 38 of 81 cases (47%) of PMTCL were positive for EBER by ISH. "By EBER-ISH, the virus was located in the tumor cells in 30 of the 38 EBV-positive cases, with the proportion of the infected cells ranging from 1% to 100%. In 18 of these cases and in the 8 cases without EBV-infected tumor cells, the virus was, respectively, either additionally or exclusively detectable in occasional nonmalignant lymphoid bystander cells."

Sinonasal T-cell lymphoma in the differential diagnosis of lethal midline granuloma using in situ hybridization for Epstein-Barr virus RNA. M Dictor, A Cervin, O Kalm, E Rambech. Mod Pathol 1996 Jan;9(1):7-14.

[Two cases of lethal midline granuloma thought to be of natural killer cell origin]. S Tamura, N Yamanaka, T Saito, I Takano, M Hotomi, M Yokoyama. Nippon Jibiinkoka Gakkai Kaiho 1996 Jan;99(1):46-53.

Epstein-Barr virus in T and natural killer (NK) cell non-Hodgkin's lymphomas. P Kanavaros, J Briere, JF Emile, P Gaulard. Leukemia 1996 Jun;10 Suppl 2:s84-s87. Review.

[Epstein-Barr virus infection in midline malignant reticulosis]. W Liu, J van Gorp, G Li. Zhonghua Zhong, Liu, Za Zhi 1997 Jan;19(1):49-52.

[Clinical characteristics of Epstein-Barr virus-associated natural killer cell lymphoma/leukemia]. K Kawa. Nippon Rinsho 1997 Feb;55(2):424-428.

Natural killer cell lymphoma/leukemia: pathology and treatment. YL Kwong, AC Chan, RH Liang. Hematol Oncol 1997 May;15(2):71-79. Review. "A consistent association with monoclonal Epstein-Barr virus infection in the tumour cell has been observed... Clinically, most cases occur in the nasal area and upper aerodigestive tract. However, occurrence in non-nasal sites such as the skin, gastrointestinal tract and testis is also observed."

Nonnasal lymphoma expressing the natural killer cell marker CD56: A clinicopathologic study of 49 cases of an uncommon agressive neoplasm. KC John, VC Sin, KF Wong, CS Ng, WYW Tsang, CH Chan, MMC Cheung, WH Lau. Blood 1997 Jun 15;89(12):4501-4513. "The nasal-type NK/T-cell lymphoma show distinctive clinicopathologic features and a very strong association with EBV."

Angiocentric T-cell lymphoma presenting as lethal midline granuloma. PY Lee, NJ Freeman, J Khorsand, MA Weinstock. Int J Dermatol 1997 Jun;36(6):419-427.

[Detection of Epstein-Barr virus DNA in malignant lymphomas]. N Kuljic-Kapulica. Vojnosanit Pregl 1997 Sep;54(5):465-468.

Integrated and episomal forms of Epstein-Barr virus (EBV) in EBV associated disease. K Oshima, J Suzumiya, M Kanda, M Kikuchi. Cancer Lett 1998 Jan 9;122(1-2):43-50.

[Epstein-Barr virus infection and expression of T-cell intracellular antigen-1 (TIA-1) in intestinal T-cell lymphoma.] X Ren, W Liu, G Li, F Li, S Zhang. Zhonghua Bing Li Xue Za Zhi 1999 Oct;28(5):348-351. "Intestinal T-cell lymphoma may be an EBV-associated extranodal NK/T cell lymphoma."

Sinonasal lymphoma: a clinicopathologic analysis of 58 cases from the Massachusetts General Hospital. I Cuadra-Garcia, GM Prouix, CL Wu, CC Wang, BZ Pilch, NL Harris, JA Ferry. Am J Surg Pathol 1999 Nov;23(11):1356-1369.

Epstein-Barr virus (EBV)-infected cells were frequently but dispersely detected in T-cell lymphomas of various types by in situ hybridization with an RNA probe specific to EBV-specific nuclear antigen 1. T Yamamoto, Y Nakamura, K Kishimoto, H Takeuchi, M Shirakata, T Mitsuya, K Hirai. Virus Res 1999 Dec 1;65(1):43-55. "Using ISH with improved antisense RNA probe specific to EBNA-1 mRNA, the virus was detected in 19 (59%) of 32 cases, whereas the EBER1 transcript was found in only 15 (47%) of 32 cases by conventional EBER-ISH, resulting in 21 EBV-positive cases (66%) by combining the two methods."

Skin is the frequent site for involvement of peripheral T-cell and natural killer cell lymphomas in Korea. KH Cho, WW Choi, CS Youn, CW Kim, DS Heo. J Dermatol 2000 Aug;27(8):500-507.

Epstein-Barr virus-infected natural killer cell leukemia. K Akashi, S Mizuno. Leuk Lymphoma 2000 Dec;40(1-2):57-66. Review; discussion of hemophagocytic lymphohistiocytosis.

(No title). M Koch, GJ Blatterspiel, G Niedobitek, J Constantinidis. Laryngorhinootologie 2001 Jul;80(7):410-415. Case & review.

Diagnostic and prognostic implications of circulating cell-free Epstein-Barr virus DNA in natural killer/T cell lymphoma. KI Lei, LY Chan, WY Chan, PJ Johnson, YM Lo. Clin Cancer Res 2002 Jan;8(1):29-34. "Plasma EBV DNA, as measured by real-time quantitative PCR, is a useful tumor marker for diagnosis, disease monitoring, and prediction of outcome in patients with NK/T cell lymphoma."

Epstein-barr virus-associated non-Hodgkin's lymphoma of B-cell origin, Hodgkin's disease, acute leukemia, and systemic lupus erythematosus: a serologic and molecular analysis. W Mitarnun, J Pradutkanchana, S Takao, V Saechan, S Suwiwat, T Ishida. J Med Assoc Thai 2002 May;85(5):552-9. In 58 patients, "EBV internal repeat-1 region (IR-1) in peripheral blood CD3+ cells was detected in 10 of 14 patients (71.5%) with NHL-B, 3 of 8 patients (37.5%) with Hodgkin's disease, 1 of 6 patients (16.7%) with acute leukemia, 4 of 9 patients (44.5%) with SLE, and was not detected in any of the 21 patients with other diseases."

Primary nasopharyngeal non-Hodgkin lymphoma and its relationship with Epstein-Barr virus infection. B Zhang, Y Zong, J He, B Zhong, S Lin. Chin Med J (Engl) 2003 Jun;116(6):913-917. "The percentages of EBV infection differed among the 3 major immunophenotypes (B cell: 11.36%, 5/44; peripheral T cell: 81.82%, 18/22; NK/T cell: 100%, 7/7)."

Nasal NK/T cell lymphoma in Taiwan: a clinicopathologic study of 22 cases, with analysis of histologic subtypes, Epstein-Barr virus LMP-1 gene association, and treatment modalities. TT Kuo, LY Shih, NM Tsang. Int J Surg Pathol 2004 Oct;12(4):375-387. "All 22 cases were positive for EBV by polymerase chain reaction and Epstein-Barr virus early RNA (EBER) in-situ hybridization."

Epstein-Barr viral infection in extranodal lymphoma of the head and neck: correlation with prognosis and response to treatment. AA Bahnassy, AR Zekri, N Asaad, S El-Houssini, HM Khalid, LM Sedky, NM Mokhtar. Histopathology 2006 Apr;48(5):516-528. "The study included 50 PELHN (11 cases in the nose and paranasal sinuses, 11 in the nasopharynx, 13 in the tonsils, seven in the oropharynx and eight in the oral cavity), five reactive lymph nodes, 15 normal nasopharyngeal tissue and 25 throat washes of healthy subjects from Egypt.... EBV was detected in 90% and 70% of the cases using EBER in situ hybridization and PCR, respectively. All cases of nasal type lymphoma were positive for EBV."

Tissue markers of Epstein-Bar virus (EBV) infection in B-cell non-Hodgkin's lymphomas. A Kasprzak, R Spachacz, A Hałoń, M Jeleń, K Stefańska, J Wachowiak, E Trejster, M Zabel. Med Wieku Rozwoj 2006 Jul-Sep;10(3 Pt 1):639-648. Archive tissue material from 26 children and from 27 adults with B-cell NHLs, using immunocytochemical techniques, in situ hybridisation, and PCR. "The detectability and expression of EBV infection were significantly higher in children with B-cell NHLs as compared to adult patients. Expression of EBNA2 and LMP1 and that of EBERs in B-cell NHLs involved mainly cells of CD20(+) phenotype. Positive correlation was confirmed between expression of EBNA2 and LMP1 as well as between expression of the two proteins and EBERs in children with B-cell NHLs. Also in children with B-cell NHLs, type III latency form dominated. In adults the latency forms were more variable. We have demonstrated a novel form of EVB latency with no EBERs expression, noted in children as well as in adults with B-cell NHLs."

[Nasal and pharyngeal non-Hodgkin lymphomas and their relationship with Epstein-Barr virus: a report of 158 cases]. YJ He, XS Jia, K Hasui, EH Wang, AG He. Zhonghua Bing Li Xue Za Zhi 2007 Feb;36(2):94-97. "Among 99 cases studied by EBER-1 in situ hybridization, a positive detection was seen in 70/71 cases (98.6%) of extranodal NK/T cell lymphoma (nasal type), 8/12 cases (66.7%) of T cell lymphoma, and 7/16 cases (43.8%) of B cell lymphoma."

Nasal natural killer/T-cell lymphoma and its association with type "i"/XhoI loss strain Epstein-Barr virus in Chile. ME Cabrera, Y Eizuru, T Itoh, C Koriyama, Y Tashiro, S Ding, S Rey, S Akiba, A Corvalan. J Clin Pathol 2007 Jun;60(6):656-660. 7 out of 9 (78%) of WHO-criteria nasal NK/T-cell lymphomas were positive for EBV.

EBV viral load in tumor tissue is an important prognostic indicator for nasal NK/T-cell lymphoma. PP Hsieh, CL Tung, AB Chan, JB Liao, JS Wang, HH Tseng, HH Su, KC Chang, CC Chang. Am J Clin Pathol 2007 Oct;128(4):579-584. 19 cases. "Patients with a low EBV viral load (<1 copy per cell) more frequently survived for more than 2 years compared with patients with a high EBV viral load (>/=1 copies/cell) (7/7 vs 3/9; P = .014; Fisher exact test). Furthermore, the patients with low EBV viral loads had a better overall survival than patients with high viral loads (50% accumulative survival: not reached vs 4-5 months; Kaplan-Meier survival analysis; P = .049). In contrast, the overall survival of the patients did not correlate with the extent of lesion, age, stage, necrosis, histologic subtypes, CD56 expression, or angiocentric or angiodestructive growth pattern."

Epstein-Barr virus infection and risk of lymphoma: immunoblot analysis of antibody responses against EBV-related proteins in a large series of lymphoma subjects and matched controls. S de Sanjosé, R Bosch, T Schouten, S Verkuijlen, A Nieters, L Foretova, M Maynadié, PL Cocco, A Staines, N Becker, P Brennan, Y Benavente, P Boffetta, CJ Meijer, JM Middeldorp. Int J Cancer 2007 Oct 15;121(8):1806-1812. 1,085 incident lymphoma cases from Spain, France, Germany, Czech Republic, Italy and 1,153 age, sex and country matched controls. An abnormal reactive pattern to EBV was observed in 20.9% of 2,238 included subjects with an increased proportion of cases presenting ab_EBV as compared to the control population (23.9% vs. 18.0% p = 0.001). Ab_EBV positivity was a risk factor for all lymphomas combined (odds ratio [OR] = 1.42, 95% confidence interval [CI]=1.15-1.74), and specifically for chronic lymphocytic leukaemia (OR = 2.96, 95%CI = 2.22-3.95).

Correlation of immunophenotype of sinonasal non-Hodgkin's lymphoma to Epstein-Barr virus infection. YF Feng, QL Wu, YS Zong. Ai Zheng 2007 Nov;26(11):1170-1176. "Seventy-one sinonasal NHLs were found in all 1 412 NHLs (71/1 412, 5.03%). Only 57 out of the 71 NHL biopsy tissues were suitable for this study. The median age of the patients was 50 years (ranged from 3 to 75 years). There were 38 males and 19 females. Forty-four sinonasal NHLs (44/57, 77.19%) were NK/T-cell lymphoma, nasal type, all of which were infected with EBV."

Quantitative analysis of cell-free Epstein-Barr virus DNA in the plasma of patients with peripheral T-cell and NK-cell lymphomas and peripheral T-cell proliferative diseases. S Suwiwat, J Pradutkanchana, T Ishida, W Mitarnun. J Clin Virol 2007 Dec;40(4):277-283. Cell-free EBV DNA was detected in 32/38 (84%) of peripheral T-cell and NK-cell lymphoma patients and 5/7 (71%) of peripheral T-cell proliferative disease patients, but not in the 45 controls.

Mechanisms

Arginine butyrate-induced susceptibility to ganciclovir in an Epstein-Barr induced lymphoma. SJ Mentzer, J Fingeroth, JJ Reilly, SP Perrine, DV Faller, Blood Cells Mol Dis 1998 Jun;24(2):114-123. "[A]ntiviral therapy with synthetic nucleosides such as ganciclovir are ineffective because the genes that render the virus susceptible to therapy are not expressed in EBV+ lymphomas... Arginine butyrate was not only effective in inducing EBV thymidine kinase transcription, but also acted synergistically with the antiviral agent ganciclovir to inhibit cell proliferation and decrease cell viability."

Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. N Khan, A Hislop, N Gudgeon, M Cobbold, R Khanna, L Nayak, AB Rickinson, PA Moss. J Immunol 2004;173(12):7481-7489. "Interestingly, the effect of age upon EBV-specific responses depends upon donor CMV sero-status. In CMV seropositive donors, the magnitude of the EBV-specific immune response is stable with age, but in CMV seronegative donors, the response to EBV increases significantly with age. By contrast, the influenza-specific CD8 T cell immune response decreases with age, independent of CMV status. The functional activity of the herpesvirus-specific immune response decreases in elderly donors, although the characteristic phenotypes of CMV- and EBV-specific memory populations are retained. This demonstrates that aging is associated with a marked accumulation of CMV-specific CD8 T cells together with a decrease in immediate effector function. Moreover, infection with CMV can reduce prevailing levels of immunity to EBV, another persistent virus. These results suggest that carriage of CMV may be detrimental to the immunocompetent host by suppressing heterologous virus-specific immunity during aging."

Interferon Regulatory Factor 7 Is Associated with Epstein-Barr Virus-Transformed Central Nervous System Lymphoma and Has Oncogenic Properties. L Zhang, J Zhang, Q Lambert, CJ Der, L Del Valle, J Miklossy, K Khalili, Y Zhou, JS Pagano. J Virol 2004 Dec;78(23):12987-12995.

LMP1 strain variants: biological and molecular properties. BA Mainou, N Raab-Traub. J Virol 2006 Jul;80(13):6458-6468. "LMP1 can activate a wide array of signaling pathways, including phosphatidylinositol 3-kinase (PI3K)-Akt and NF-kappaB. Six sequence variants of LMP1, termed Alaskan, China 1, China 2, Med+, Med-, and NC, have been identified, and individuals can be infected with multiple variants. The frequencies of detection of these variants differ for various EBV-associated malignancies from different geographic regions.... While all the variants activated the PI3K-Akt signaling pathway to similar extents, the Alaskan, China 1, and Med+ variants had limited binding to the E3 ubiquitin ligase component homologue of Slimb and had slightly enhanced NF-kappaB signaling."

A molecular link between malaria and Epstein-Barr virus reactivation. A Chêne, D Donati, AO Guerreiro-Cacais, V Levitsky, Q Chen, KI Falk, J Orem, F Kironde, M Wahlgren, MT Bejarano. PLoS Pathog 2007 Jun;3(6):e80. "We show that CIDR1alpha binds to the EBV-positive B cell line Akata and increases the number of cells switching to the viral lytic cycle as measured by green fluorescent protein (GFP) expression driven by a lytic promoter. The virus production in CIDR1alpha-exposed cultures was directly proportional to the number of GFP-positive Akata cells (lytic EBV) and to the increased expression of the EBV lytic promoter BZLF1. Furthermore, CIDR1alpha stimulated the production of EBV in peripheral blood mononuclear cells derived from healthy donors and children with BL. Our results suggest that P. falciparum antigens such as CIDR1alpha can directly induce EBV reactivation during malaria infection that may increase the risk of BL development for children living in malaria-endemic areas. To our knowledge, this is the first report to show that a microbial protein can drive a latently infected B cell into EBV replication."

Epstein-Barr Virus Infection of Langerhans Cell Precursors as a Mechanism of Oral Epithelial Entry, Persistence, and Reactivation. DM Walling, AJ Ray, JE Nichols, CM Flaitz, CM Nichols. J Virol 2007 Jul;81(13):7249-7268. "In this study, we present the first evidence demonstrating that EBV latently infects a unique subset of blood-borne mononuclear cells that are direct precursors to Langerhans cells and that EBV both latently and productively infects oral epithelium-resident cells that are likely Langerhans cells. These data form the basis of a proposed new model of EBV transition from blood to oral epithelium in which EBV-infected Langerhans cell precursors serve to transport EBV to the oral epithelium as they migrate and differentiate into oral Langerhans cells. This new model contributes fresh insight into the natural history of EBV infection and the pathogenesis of EBV-associated epithelial disease."

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cast 08-10-08