HEALTHIMPLICATIONSOFVIRUSESFROM qg SOUTHAMERICANMONKEYS

The three papers published below were presented at a Special Symposium on Viruses of South American Monkeys organized by the Pan American Health Organization in cooperation with the New England Regional Primate Research Center of Harvard Medical School. A full selection of papers presented at the meetings is contained in the book International Movement of Animals published by the Pan American Health Organiza- tion.

HERPES-LIKE SIMIAN VIRUSES : RETROSPECTIVE AND PROSPECTIVE CONSIDERATIONS’

Thomas H. Weller, M.D.2

The introduction of improved tissue culture polioviruses stimulated the importation of tens techniques for the study of viral pathogensof of thousands of Old World monkeys into the man has resulted in an explosive growth of United States and Europe. Those engagedin virologic knowledge. Progressin the past two vaccine production found that monkeys and decades has been characterized by successive monkey tissueswere essentialfor viral propaga- episodesof intense scientific activity and intel- tion and for testing safety. lectual excitement, each stemming from isola- As a consequenceof work based primarily tion of a new agent or from development of on Old World monkeys, a considerablebody of new methodologic approaches. As a conse- knowledge has accumulated regarding simian quence of the cumulative efforts of many viruses. In a recent review, Hull recorded 57 scientists, we now possess effective vaccines for serotypes of simian agents representing seven the control of poliomyelitis, measles,rubella, different virus families (I). During this period and mumps. the occupational hazards of B virus The studies on poliomyelitis, perhapsmore (Herpesvirus simiae) were recognized, and the than generally realized, established a basic disconcerting discovery was made that some pattern for applied virologic researchthat in- lots of polio vaccine contained potentially cluded the preferential use of Old World mon- oncogenicSV40 virus. keys as experimental subjects. Paradoxically, That new problems due to simian viruses the in vitro procedures that initially were might arise at any time was dramatically illus- heralded as emancipating the researcherfrom trated in 1967 by the Marburg incident, in dependence on monkeys for the study of which seven human deaths followed exposure to a previously unrecognized agent infecting a shipment of African green monkeys. Yet, con- IPaper presented at the II International Sympo- sidering that tens of thousands of monkeys sium on Health Aspects of the International Move- ment of Animals (Special Symposium on Viruses of were utilized and that millions of doses of South American Monkeys) held in Mexico City on vaccine derived from monkey cells have been 11-13 August 1971. Previously published in Scientific Publication PAHO 235 (1972), pp. 121-123. distributed, it is amazing that the iatrogenic 2Richard Pearson Strong Professor of Tropical exposure of man to these simian viruses has Public Health and Chairman of the Department, Harvard School of Public Health, Harvard University, been relatively free of unforeseen conse- Boston, Massachusetts. quences. The excellent record for containing 55 56 ENGLISH EDITION-BOLETIN DE LA OSP . Vol. VII, No. 1, 1973 the hazards of indigenous viruses of Old World squirrel monkey has the capacity to induce monkeys reflects vigilance that is now basedon lymphomas in other New World primates. The an extensive body of knowledge accumulated process is remarkably malignant, with owl over two decades. monkeys and marmosets succumbing 13-28 Currently, scientistsinterested in a variety of days after inoculation (5). Further, Herpesvivus infectious agentsare again enjoying the excite- saimiri can induce a lymphomatous responsein ment and acceleratedprogress associated with animals as taxonomically distant as rabbits. The introduction of a new methodologic approach- obvious question is, What would it do in man? in this instance based on the increasing availa- These observationscome at a time when the bility for researchpurposes of severalgenera of herpes-relatedviruses of man are the subjectsof New World monkeys. Brief reference to se- increasing interest in terms of their oncogenic lected studies will document the rapid accept- potential and because of their unique host- ance of this new researchresource by workers parasite relationships. The capacity to establish outside the field of classicalvirology. In 1966, a persistent latent infection, with or without Young et al., employing Aotus, reported the episodesof renewed clinical activity, is a little transmissionof Plasmodium vivax to monkeys, understood characteristic of the herpes group and the following year Geiman and Meagher of viruses. This attribute, per se, is a matter of infected Aotus with Plasmodium falciparum primary concern in the development of attenu- (2). Other New World monkeys have more ated live viral vaccinesagainst membersof the recently been infected with malaria parasitesof herpesgroup. man. Thus, for the first time the pressing For example, although we isolated varicella problem of chloroquine-resistantmalaria can be virus in 1953 (6), chickenpox persistsunaltered studied in a convenient primate model. in our midst. But how, in view of the host In the area of helminthology, Aotus has specificity of varicella virus, would one safely recently been shown to be susceptible to test an attenuated varicella vaccine? Decadesof infection with the three species of human observing the human experimental host would schistosomes(3). be mandatory to assurethat the latent vaccine Experimental trachoma in Old World mon- virus did not subsequentlyresurface in the form keys is a relatively benign process.However, as of a peculiarly virulent attack of herpeszoster. recently reported by Bell and Fraser, inocula- Members of another highly host-specific tion of the eye of the owl monkey induces family- of the herpes group of viruses, the severeclinical and microbiological disease(4). cytomegalovirusesof man, can produce congen- The owl monkey therefore supplants other ital brain damage and a variety of clinical animal models for testing experimental tracho- syndromes ranging from infectious hepatitis to ma vaccines. an infectious mononucleosis-likefebrile illness. These examples not only emphasize the Indeed, the number of infants damagedas a new-found potential of New World monkeys as consequenceof congenital cytomegaloviral in- subjects for researchin nonvirologic areas,but fection probably greatly exceeds the number also indicate the rapidly expanding chancesfor affected by rubella virus (7). As with varicella, human contact with a new and little under- in studying the human cytomegaloviruseswe stood spectrumof simian viruses. lack a susceptible experimental animal. Hope- With this prologue we approach the topic of fully, systematic screening of the New World our symposium, namely, the viruses of South primates will reveal animals that are susceptible American monkeys. This meeting is a conse- to varicella and the human cytomegaloviruses. quence of the unexpected, important, and yet In these introductory remarks I have omit- disturbing discovery by our chairman, Dr. Luis ted reference to Epstein-Barr virus and to the Melendez, and his co-workers that a herpes significant data indicating an etiologic relation virus (Herpesvints saimiri) recovered from the of this agent to infectious mononucleosis, Weller . HERPES-LIKE SIMIAN VIRUSES 57

Burkitt’s tumor, and nasopharyngeal carcino- episodes of intense scientific activity and intel- ma. Nor have I referred to still controversial lectual excitement, resulting from isolation of data bearing on the causalor casualrelationship some new agent or development of new meth- odologic approaches. Scientists interested in a of Herpesvirus hominis Type 2 and human variety of infectious agents are now taking cervical carcinoma, or to the herpesvirus re- advantage of another new approach-use of sponsible for Marek’s disease of chickens, or several genera of New World monkeys that have that associatedwith Lucke tumor of frogs. become available for research. I have instead chosen to emphasizethat we The demonstration that herpesviruses of some of these New World monkeys can induce are entering an exciting new period of virologic rapidly fatal malignant disease in animals is investigation. For two decades, following a adding impetus to work on viruses and cancer, pattern established by research on poliomyeli- and is providing important new approaches to tis, we utilized, of necessity,in vitro techniques chemotherapy and immunologic control of based on the availability of Old World mon- malignant disease. However, until the hazards of the new oncogenic herpesviruses are defined, keys. Currently, with the increasing introduc- distribution of the new agents should be moni- tion of New World primates as researchtools, a tored and limited to investigators competent new spectrum of challenging investigative op- and equipped to deal with dangerous viruses. portunities-and of hazards to human health- is evolving. The demonstration that herpesvi- REFERENCES ruses of New World monkeys will induce rapidly fatal malignant diseasein primates as (0 Hull, R.N.“The Significance of Simian Viruses to well as in unrelated mammalswill add impetus the Monkey Colony and the Laboratory Investi- to work on the viral etiology of cancer in gator.” In Experimental Medicine and Surgery in Primates, ed. by E. 1. Goldsmith and J. general, and will provide important new ap- Moor-Jankowski. Ann N Y Acad Sci 162: proaches to the chemotherapy and irnmunol- 412-482,196P. ogic control of malignant disease. (2) Geiman, Q. M., and M. J. Meagher. “Susceptibil- But until the hazards for man of the new ity of a New World Monkey to Plasmodfum oncogenic herpesvirusesare defined, distribu- falcipatum from Man.” Nature 215: 437, 1961. (3) Erickson, D. G., F. vonlichtenberg, E. H. Sadun, tion of the new agents should be monitored and H. L. Lucia, and R. L. Hickman. “Comparison limited to investigators competent and of Schistosoma haematobium, S. mansoni, and equipped to deal with dangerousviruses. We are S. japonicum Infections in the Owl Monkey, now forced to develop policies designed to Aotus trivirgatus.” J Parasit 57: 543-558, 1971. protect the health of the public on the basisof (4) Bell, S. D., and C. E. 0. Fraser. “Experimental Trachoma in Owl Monkeys.” Amer J Trop Med an educated guess rather than on the rational 18: 568-572, 1969. evaluation of scientific facts. However, the (3 Melendez, L. V., R. D. Hunt, M. D. Daniel, F. G. hypothetical picture of an unknowingly in- Garcia, and C. E. 0. Fraser. ‘Herpesvirus fected scientist who is excreting an oncogenic saimiri. II. Experimentally Induced Malignant agent at home and in his community compels Lymphoma in Primates.” Lab Anim Care 19: 378-386, 1969. vigilance. (6) Weller, T. H. ‘Serial Propagation in Vitro of Agents Producing Inclusion Bodies Derived from Varicella and Herpes Zoster.” Proc Sot SUMMARY Exp Biol Med 83: 340-346, 1953. (7’) Weller, T. H. “The Cytomegaloviruses: Ubiqui- Rapid progress has been made in studying tous Agents with Protean Clinical Manifesta- man’s viral pathogens over the past two dec- tions.” New Eng J Med 285: 203-214,267-274, ades. This has been characterized by successive 1971.