[CANCER RESEARCH33, 1424 1426, June 1973] Simian Herpesviruses1

Friedrich Deinhardt, Lawrence A. Falk, and Lauren G. Wolfe Departments of Microbiology. Rush-Presbyterian-Si. Luke's and University of Illinois Medical Centers, Chicago, Illinois 60612

The work presented by Dr. Henle gives current evidence lymphoproliferative disease in several nonhuman primate of an association between EBV3 and Burkitt's lymphoma genera other than their natural hosts (1, 7, 12-14, 17). These and possibly also nasopharyngeal carcinoma. In addition, it diseases are almost always fatal for infected animals, and has been proved beyond doubt that EBV is responsible for horizontal transmission, which has not been observed for infectious mononucleosis (a self-limited lymphoproliferative HVS in the experimental host species, has been claimed for disease) and that EBV can transform lymphocytes in vitro. HVA (6). In HVS-infected animals, which have been Such transformed lymphocytes then proliferate indefinitely. studied more extensively, no infectious virus or viral The author's data on 2 simian viruses that are similar to proteins can be found at any time between infection and EBV are as follows. Both HVS and HVA were isolated first death. However, cultivation of the neoplastic cells in vitro by Melendez et al. (l l, 15) from normal, apparently healthy results in an almost immediate derepression of the viral squirrel or spider monkeys, respectively. It was later shown genome, and viral antigens and infectious virus are pro (3), at least for HVS, that generally the agent does not cause duced within 24 to 72 hr after explantation (5). Permanent overt disease in its natural hosts, the squirrel monkeys and cell culture lines have been established from the lymphomas that it is transmitted horizontally. Epidemiological data or from abnormal peripheral lymphocytes (4, 16). Studies of indicate that a similar situation exists for HVA. Infection such lines (9, 15) showed, at least in marmosets (a) that the with either HVS or HVA apparently occurs early in life disease is multiclonal (2, 9); (b) that these lines usually but and, once infected, animals remain virus carriers for life. not always produce a small amount of virus; and (c) that the Virus or virus proteins cannot be demonstrated in carrier degenerating, virus-producing cells contain virus antigens animals, but the viral genome is consistently activated when (4, 16) in a fashion very similar to the expression of EBV in the lymphocytes of carrier animals are cultured in vitro lymphoblastic cell lines established from infectious mono (either alone, or together with susceptible cells). The nucleosis patients or from Burkitt's lymphomas. Attempts frequency of isolation of HVS and HVA and the presence of to demonstrate any activation of an RNA virus in the antiviral antibodies in experiments in our laboratory in HVS-induced malignant lymphoproliferative disease have various groups of squirrel or spider monkeys, respectively, failed. are given in Tables 1 and 2. The 4 viruses we isolated from Recently, it was shown (8) that HVS-infected cells con spider monkeys are presumed to be HVA, on the basis of tain at least 2 and possibly 3 different antigens which may their host range in vitro (15) and their oncogenicity for be equivalent to the early and late antigens of EBV. marmoset monkeys. However, the antigenic relationship Squirrel monkeys develop antibodies to both the aarly and between these viruses and HVS isolated by Melendez et al. late HVS antigens after their primary infection, but only (15) remains to be established. Serological studies in our the antibodies versus the late antigens persist, whereas the laboratory suggest a cross-reactivity between HVS and antibodies to the early antigens decline in 6 months to 1 HVA. Sera from marmoset, owl, and squirrel monkeys that year. Antibodies to both antigens do not appear as rapidly had been experimentally infected with HVS developed in experimentally infected animals of other genera, and antibodies to both HVS and HVA, as demonstrated by antibodies versus the early antigens may not develop at all immunofluorescence tests. Preinoculation sera from these or may develop only during the terminal stage of the dis animals contained no antibodies to either virus. Neutraliza ease. tion studies with these sera are in progress. Table 3 The similarity between HVS and HVA and EBV is strik summarizes the incidence of HVS and HVA antibodies in ing. Virus expression in vivo or in vitro and antibody re some nonhuman primate genera. sponses of infected hosts are almost identical for HVS and Experimentally, HVS and HVA both induce malignant EBV and probably also for HVA. EBV produces a self- limited lymphoproliferative disease after primary in fection and results in a lifelong carrier state. HVS and 1Presented at the American Cancer Society Conference on Herpesvirus HVA infection produced only a subclinical disease (if any), and Cervical Cancer, December 8 to 10, 1972. Key Biscayne, Fla. This study was supported by Research Contract NIH 71-2032, within the which results in a permanent carrier state in the natural Special Virus Cancer Program of the National Cancer Institute; Training hosts. EBV is probably responsible for the development Grant TOI-AI-2053, National Institute of Allergy and Infectious Diseases: of Burkitt's lymphoma and nasopharyngeal carcinoma, and Grant RR-05477 from the General Research Support Branch, Division possibly in conjunction with as yet undefined cofactors, of Research Facilities and Resources, NIH, USPHS. 1Presented by. whereas no late sequels of HVS or HVA in their natural 'The abbreviations used are: EBV, Epstein-Barr virus: HVS, Herpes- hosts have been reported. However, even if squirrel or spider monkeys develop a Burkitt's lymphoma-like dis- virus saimirí;HVA, Herpesvirus áteles.

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Table 1 HVS isolation from colony-born and imported squirrel monkeys and determination of HVS antibodies No. of viruses isolated"/ No. of specimens with HVS Origin Age no. of specimens tested antibodies'/no, tested

Colony-bornImportedBowman mo.4-6 mo.< 1yr>2 119/19 yr>3 (1:4167/67(1:4 yr0•>?>2 116/22

SchoolLincolnGray Medical (1:414/6 ZooPet Park (>4)5/8 storeTarpon (>4)20/20(1:4 Zoo<2 yr0/50/77/168/1933/677/228/106/816/200/20/76/16(1:4 1:64)r:128):128):64)¡128) 11Determined by cocultivation of whole blood or separated lymphocytes on monolayers of susceptible cells. * Determined by indirect fluorescent antibody tests. ' Numbers in parentheses, range of liters.

Table 2 H VA isolation from imported spider monkeys and determination of antibodies to H VA and H VS No. of specimens with No. of viruses antibodies'/no, tested isolated"/no. of blood specimens Age tested HVA antibodies HVS antibodies

Juvenile (< 1 yr) 1/4 7/14 4/14 Adult 3/14 7/10 7/10 " Determined by cocultivation of whole blood or separation of lymphocytes on monolayers of susceptible cells. *Determined by indirect fluorescent antibody tests with serum diluted 1:4. ease from HVS or HVA infection with the frequency that Table 3 humans develop Burkitt's lymphoma, it is unlikely that a HVS and HVA serum antibodies in New World monkeys case would have been identified yet. Attempts to induce No. antibody lymphomas in squirrel monkeys carrying HVS by positive°/no.tested immunosuppression, chronic malaria, or other manipula tions are under way. If they are successful, further GeneraÕteles evidence for the association of EBV with Burkitt's lym spider)Õtelesfusciceps (black phoma and an understanding of the pathogenesis would spider)Cebusgeoffroyi (red have been gained. However, even without these data, the face)Saguinuscapucinus (white ability of HVS and HVA to induce malignant lymphoma (marmoset)ImportedColony-bornAotussp. and lymphoblastic leukemias in several nonhuman primate genera and the presence of similar herpesviruses and (owl)Lagoihrixtrivirgalui associated malignant disease in other animal species (dis sp. (woolly)HVS3/5I/I0/120/940/593/193/4HVA0/100/41/103/4 cussed in other reports in this Conference), already com 1Determined by indirect immunofluorescence tests. prise strong supporting evidence of the association between EBV and Burkitt's lymphoma and possibly also naso- pharyngeal carcinoma in humans. It is still puzzling why perhaps there is a difference at the molecular level of the HVS and HVA are nonpathogenic in their natural hosts but cell-virus interaction (i.e., insertion of the virus genome are highly oncogenic in quite closely related species. Biolog results more consistently in transformation of cells in ically, this makes sense, of course, as neither the virus nor experimental animals than in transformation of cells in the the host species could survive if infection were always natural hosts). followed by fatal disease, but the mechanism responsible for Besides offering "brain teasers," the great importance of the degree of pathogenicity is not known. Maybe the natural these animal systems (particularly of the nonhuman primate hosts were selected by their ability to react with a rapid and systems) lies in the opportunities they offer for studying the efficient immune response, thus eliminating any trans pathogenetic mechanisms of malignant disease induced by formed cells immediately and restricting further virus herpesviruses. The use of these models for therapeutic spread (i.e., squirrel monkeys react earlier and better to the studies may even lead eventually to a better control of these early and late antigens than do the experimental hosts), or diseases in humans.

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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1973 American Association for Cancer Research. Simian Herpesviritses References in Marmoset Monkeys. J. Nati. Cancer Inst. 50: 331 337, 1973. 10. Melendez, L. V., Castellanos, H„Barahona, H. H., Daniel, M. D., I Ablashi, D. V., Loeb, W. F., Valerio, M. G., Adamson, R. H., Hunt, R. D., Fraser, C. E. O., Garcia, F. G., and King, N. W. Two Armstrong, G. R., Bennett, D. G., and Heine, U. Malignant Lym New Herpesviruses from Spider Monkeys (Õtelesgeoffroyi). i. Nati. phoma with Lymphocytic Leukemia in Owl Monkeys Induced by Cancer Inst., 49: 233 237, 1972. Herpesvirus saimirí.J. Nati. Cancer Inst., 47: 837 856, 1971. 11. Melendez, L. V., Daniel, M. D., Hunt, R. D., and Garcia, F. G. An 2. Chu, E. W., and Rabson, A. S. Chimerism in Lymphoid Cell Culture Apparently New Herpesvirus from Primary Kidney Cultures of the Line Derived from Lymph Node of Marmoset Infected with Herpes- Squirrel Monkey (Saimirísciureus). Lab. Animal Care. 18: 374-381, virus saimirí.¡.Nati. Cancer Inst., 48: 771 775, 1972. 1968. 3. Falk, L., Wolfe, L. G., and Deinhardt. F. Epidemiology of Herpesvirus 12. Melendez, L. V., Hunt, R. D., Daniel, M. D., Blake, B. J., and Garcia, saimiríInfection in Squirrel Monkeys. Med. Primato!., in press. F. G. Acute Lymphocytic Leukemia in Owl Monkeys (Aolus 4. Falk, L. A., Marc/ynska, B., Wolfe, L., and Deinhardt, F. Characteri trivirgatus) Inoculated with Herpesvirus saimirí. Science, 171: 1161-1163, 1971. zation of Lymphoid Cell Lines Established from Herpesvirus saimirí (HVS)-infected Marmosets. Abstracts of the Annual Meeting of the 13. Melendez, L. V., Hunt, R. D., Daniel, M. D., Fraser, C. E. O., Garcia, American Society for Microbiology, p. 191, 1972. F. G., and Williamson, F. D. Lethal Reticuloproliferative Disease 5. Falk, L. A., Wolfe, L. G., Hoekstra, J., and Deinhardt, F. Demonstra Induced in Cebus albifrons Monkeys by Herpesvirus saimirí.Intern. J. tion of Herpesvirus saimiri-assocmled Antigens in Peripheral Lym Cancer, 6: 431-435. 1970. phocytes from Infected Marmosets during in Vitro Cultivation. J. 14. Melendez, L. V., Hunt. R. D., Daniel, M. D., and Trum, B. F. New Nati. Cancer Inst., 48: 523-530, 1972. World Monkeys, Herpes Viruses and Cancer. In: H. Bainer and 6. Hunt. R. D., Melendez. L. V., Garcia, F. G., and Trum, B. F. W. I. B. Beveridge (eds.). Infections and Immunosuppression in Sub Herpesvirus aleles Lymphoma in Cotton-topped Marmosets (Sagui- human Primates, pp. 111-117. Denmark: Copenhagen, Munksgaard, nus uedipus). J. Nati. Cancer Inst., 49: 1631 1640, 1972. 1970. 7. Hunt. R. D., Melendez, L. V.. King, N. W„and Garcia. F. G. 15. Melendez, L. V., Hunt, R. D., King, N. W., Barahona, H. H., Daniel. Herpesvirus saimiríMalignant Lymphoma in Spider Monkeys. J. M. D., Fraser, C. E. O., and Garcia, F. G. A New Lymphoma Virus of Med. Primatology, /: 114-128, 1972. Monkeys: Herpesvirus aleles. Nature New Bio\.,235: 182-184, 1972. 16. Rabson, A. S., O'Conor, G. T., Lorenz, D. E., Kirschstein, R. L., 8. Klein. G.. Pearson, G., Rabson, A., Ablashi, D., Falk, L., Wolfe, L., Deinhardt, F.. and Rabin, H. Antibody Reactions to Herpesvirus Legallais, F. Y., and Tralka, T. S. Lymphoid Cell Culture Line saimirí(HVS)-induced Early and Late Antigens (EA and LA) in derived from Lymph Node of Marmoset Infected with Herpesvirus HVS-infected Squirrel, Marmoset and Owl Monkey.s Intern. J. saimirí,i. Nati. Cancer Inst., 46: 1099-1109, 1971. Cancer, in press. 17. Wolfe, L. G., Falk, L. A., and Deinhardt. F. Oncogenicity of 9. Marczynska, B., Falk, L., Wolfe, L., and Deinhardt. F. Transplanta Herpesvirus saimiríin Marmoset Monkeys. J. Nail. Cancer Inst., 47: tion and Cytogenetic Studies of Herpesvirus saimiríInduced Disease 1145-1162, 1972.

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Friedrich Deinhardt, Lawrence A. Falk and Lauren G. Wolfe

Cancer Res 1973;33:1424-1426.

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