Comparative Medicine Vol 65, No 3 Copyright 2015 June 2015 by the American Association for Laboratory Animal Science Pages 232–240 Overview Endemic Viruses of Squirrel Monkeys (Saimiri spp.) Donna L Rogers,1 Gloria B McClure,1 Julio C Ruiz,2 Christian R Abee,2 and John A Vanchiere1,* Nonhuman primates are the experimental animals of choice for the study of many human diseases. As such, it is important to understand that endemic viruses of primates can potentially affect the design, methods, and results of biomedical studies designed to model human disease. Here we review the viruses known to be endemic in squirrel monkeys (Saimiri spp.). The pathogenic potential of these viruses in squirrel monkeys that undergo experimental manipulation remains largely unexplored but may have implications regarding the use of squirrel monkeys in biomedical research. Abbreviations: HTLV1, human T-cell leukemia virus type 1; HVS, herpesvirus saimiri; IPF, idiopathic pulmonary fibrosis; SaHV, Saimiriine herpesvirus; SFV, simian foamy virus; SM-CMV, squirrel monkey cytomegalovirus; SMPyV, squirrel monkey polyomavirus; SMRV, squirrel monkey retrovirus The similarity between the nonhuman primate and human ment during handling, make squirrel monkeys attractive species immune systems is a key advantage in the use of nonhuman for model development and for studies of viral pathogenesis, primates compared with other mammalian models of human which cost approximately 30% to 40% less than comparable disease.13,71,88,94,103,113,125 In addition, the diversity of environmental studies in macaques.1 The likelihood of zoonotic transmission and infectious disease agents encountered by primates is similar of infectious pathogens is considerably less than that associated to that of humans, providing nonhuman primates a comparable with macaques and the risk of Macacine herpesvirus 1 (B virus) is level of biologic complexity.1 Old World primates, such as ma- nonexistent, given that neotropical primates do not harbor this caques and baboons, and New World primates, including squir- lethal virus.1 These factors are increasingly important in the cur- rel monkeys and marmosets, are commonly used in biomedical rent climate of limited grant funding for biomedical research and research. Squirrel monkeys (Saimiri spp.) are neotropical primates emphasis on safety for laboratory personnel. The limited avail- native to the forests of Central and South America. Of the 7 spe- ability of immunologic reagents with specificity for neotropi- cies of squirrel monkey, 3 (S. oerstedii, S. vanzolinii, and S. ustus) cal primates has hindered broader use of squirrel monkeys in are classified as endangered, vulnerable to extinction in the wild, biomedical research, compared with that of the more commonly or near threatened, whereas the remaining 4 (S. boliviensis, S. used Old World primates. In addition, the small size of neotropi- cassiquiarensis, S. macrodon, and S. sciureus) are not endangered, cal primates limits the volume of blood that can be collected at although the S. cassiquiarensis albigena subspecies is near threat- any one time. To abrogate these limitations, the NIH Nonhuman ened52,81 (Figure 1). In South America, where squirrel monkeys are Primate Reagent Resource (www.nhpreagents.org) provides an indigenous, breeding colonies of S. sciureus have been maintained increasing repertoire of agents that have been characterized for at the Pasteur Institute in French Guiana and at the Oswaldo Cruz immunologic studies of neotropical primates.89 Foundation in Brazil.7,12 In the United States, the Squirrel Monkey Squirrel monkeys are used in numerous aspects of biomedical Breeding and Research Resource, an NIH-sponsored national research, including studies of viral persistence, neuroendocrinol- research resource, maintains breeding colonies for S. boliviensis ogy, infectious diseases, cancer treatments, vaccine development, boliviensis, S. sciureus sciureus, and S. boliviensis peruviensis. gene expression, and reproductive physiology.117 The similarity Squirrel monkeys adapt easily to laboratory housing and can between the squirrel monkey immune system and that of hu- be housed in smaller spaces than can Old World primates.1 Unlike mans means that, as with macaques, there is a high likelihood when working with Old World primates, particularly macaques, that research outcomes will recapitulate what occurs in human no additional personnel protective equipment is necessary when diseases.13,71,87,94 This is particularly true for the study of several working with squirrel monkeys beyond that recommended for notable infectious diseases, including malaria, Creutzfeldt–Jakob working with other New World primates.92 Their small size, disease, and human T-cell leukemia virus type 1 (HTLV1) infec- combined with the reduced need for personnel protective equip- tion.19,56,128 For these diseases, squirrel monkeys are the model sys- tem of choice for studying pathogenesis, experimental treatments, and strategies for prevention. Received: 06 Oct 2014. Revision requested: 10 Nov 2014. Accepted: 25 Jan 2015. Squirrel monkeys are recognized as some of the most suscepti- 1Department of Pediatrics, Section of Infectious Diseases, Louisiana State University Health Sciences Center, Shreveport, Louisiana, and 2Keeling Center for Comparative ble nonhuman primate species for the experimental transmission Medicine, Department of Veterinary Sciences, University of Texas MD Anderson Cancer of Creutzfeldt–Jakob disease and other transmissible spongiform Center, Bastrop, Texas. encephalopathies that cause chronic wasting disease.11,72,98,130 The *Corresponding author. Email: [email protected] 232 Endemic viruses of squirrel monkeys Figure 1. Taxonomy of Saimiri species with associated IUCN designations.52,81 experimental infection of squirrel monkeys with HTLV1 has led during immune suppression has been largely unexplored. As to their use in vaccine development and chemotherapy research such, the implications of these viruses regarding the interpreta- directed against HTLV1.44,57,58,82 In addition, squirrel monkeys are tion of data from studies that involve immune suppression in an important model for studying the immunology of malaria and squirrel monkeys are currently unknown. Therefore, for studies for testing vaccines against several Plasmodium species.19,20,68,114 involving an immune suppression component, it is prudent to Furthermore, squirrel monkeys have been used in pharmacologic monitor the blood, urine, and saliva for significant changes in research to raise HDL levels to prevent atherosclerosis and reduce the viral loads of the endemic viruses, particularly herpesvirus the risk of coronary heart disease.6 As the use of squirrel monkeys saimiri (HVS), which is ubiquitous in squirrel monkeys and is increases, especially for infectious disease research, accurate in- directly immunomodulatory.36,73 The salient characteristics of the formation about the endemic viral infections of squirrel monkeys known endemic squirrel monkey viruses are presented in Figure 2 is needed because of the potential for zoonotic transfer of these and reviewed here. viruses to humans (and vice versa) and to understand the poten- tial influence these agents may have on research involving other Herpesviruses infectious pathogens diseases and immunosuppressive drugs. Herpesviruses are present in most species of animals and are classified into 3 subfamilies α( , β, and γ) on the basis of their bio- Endemic Viruses of Squirrel Monkeys logic properties and genome sequences. Eight herpesviruses have The presence of endemic squirrel monkey viruses has been been identified in humans, and 4 analogous herpesviruses have known for over 40 y, and all primates used in biomedical re- been found in squirrel monkeys. Herpesviruses share a common search are assumed to asymptomatically harbor persistent vi- evolutionary origin and establish lifelong latency in their host, ruses, including herpesviruses and polyomaviruses.53,54,61,77,124 Of with intermittent periods of lytic replication and excretion.95 the known endemic viruses of squirrel monkeys, only Saimiriine SaHV1. The squirrel monkey alphaherpesvirus SaHV1 was herpesvirus 1 (SaHV1) is occasionally pathogenic in its natural originally named ‘herpesvirus tamarinus’ because the virus host, causing orofacial ulcers and lingual plaques.61 These lesions was initially isolated and characterized from tamarins (Sa- are mild and self-limited, occurring only sporadically in the large guinas spp.).46,80 In 1964, 2 independent reports described fatal colony of animals at the Squirrel Monkey Breeding and Research generalized disease in tamarins, marmosets, rabbits, and mice Resource. Whether any of the endemic viruses remain benign infected with this novel alphaherpesvirus;46,80 owl monkeys also 233 Vol 65, No 3 Comparative Medicine June 2015 Figure 2. Characteristics of known endemic squirrel monkey viruses. SaHV3 has been proposed as the designation, but the International Committee on Taxonomy of Viruses has not yet assigned it. HSV, herpes simplex virus; HHV8, human herpesvirus 8; EBV, Epstein–Barr virus; HCMV, human cytomegalovirus. were found to be susceptible to fatal disease after infection with genomic organization and DNA sequence, HVS is most closely SaHV1.31 Subsequent studies revealed that squirrel monkeys are related to human herpesvirus 8, also known as Kaposi sarcoma- the natural host for this virus.24,47,61 The prevalence of SaHV1 in associated herpesvirus.5,23,65 Squirrel monkeys