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ILAR Journal V38(1) 1997
Unusual Mammalian Models
Stephanie J. Buchl, Michale E. Keeling, and William R. Voss
| Stephanie J. Buchl, D.V.M., is Assistant Veterinarian and Michale E. Keeling. D.V.M., is Professor of Comparative Medicine and Department Chairman at the University of Texas M.D. Anderson Cancer Center, Department of Veterinary Sciences, Bastrop, Texas. William R. Ross, D.V.M., is Manager of Veterinary Services at Hazelton Research Products, Inc. (HRP), Kalamazoo, Michigan. |
INTRODUCTION
Nonhuman primates continue to make significant contributions to human health through their role in comparative biomedical research in vaccine development, toxicology, teratogenesis, reproduction, xenotransplantation, and infectious diseases along with their therapy (Schmidt 1972; Eichberg 1989; Dormont and others 1990; Kalter and Heberling 1995). With today's growing sophistication in research and technology there is a demand for a comparably high-quality animal model that was foreseen in 1972 (Neurauter and Goodwin 1972). In 1988, it became apparent there would be a significant future need for retrovirus- and herpes B virus-free monkeys to enable investigators to fully develop a promising simian immunodeficiency virus (SIV) monkey model (Stahl-Hennig and others 1990).
Several of the retroviruses that infect rhesus monkeys have the same biological characteristics as HIV (human immunodeficiency virus) (Lerche and others 1994). Simian retrovirus infection in rhesus monkeys is widespread and in an experimental setting produces many of the same diseases as HIV in humans. Simian retroviruses cause neoplasia, leukemias, neurological disease, and immunodeficiency syndrome in nonhuman primates (Lerche and others 1991; Daniel and others 1984, 1985; Letvin and others 1985; Lowenstine and others 1986; Murphey-Corb and others 1986; Chakrabarti and others 1987). Many of the domestic rhesus production colonies were naturally infected with simian retroviruses that would confound experimental data relevant to AIDS research. There was an obvious need to establish a sustainable resource of rhesus monkeys free of simian retroviruses (Lerche and others 1994).
In concert with the mission of the National Center for Research Resources (NCRR), of the National Institutes of Health (NIH) and as part of the AIDS animal model program, a new initiative was launched to assist the development of self-propagating specific-pathogen-free (SPF) breeding populations of rhesus monkeys. The driving force behind creating SPF rhesus monkey colonies was AIDS, which was developing into one of the most frightening infectious diseases to affect man in recent medical history.
The SIV monkey model is being used to study horizontal and vertical retroviral transmission, development and efficacy of vaccines, and disease pathogenesis (Balzarini and others 1990; Cranage and others 1990; Kitchin and others 1990). The use of the SIV monkey model is critical to the success of developing HIV vaccines and drug therapies (Axthelm and Shiigi 1990).
Elimination of retroviruses from the SIV monkey model was the primary objective in developing an SPF rhesus monkey resource, but the elimination of the Cercopithecine herpes virus 1 (Herpesvirus simiae, Herpes B virus, B virus) from this population was also a valuable goal. NCRR also recognized the value of funding companion research grants that would improve methods of nonhuman primate housing, husbandry, enrichment, and the production and development of laboratory and field tests for retro- and herpes viruses.
Herpesvirus simiae, also known as herpes B virus, is widespread within import and domestic rhesus monkey breeding populations and continues to represent a significant health threat to personnel who care for rhesus monkeys or handle their tissues (Ward and Hilliard 1994, CDC 1987a). B virus exposures caused 2 deaths in Florida in 1987, a death in Michigan in 1989, and the death of a Texas veterinarian in 1991 (CDC 1987b, 1989, 1991; Scinicariello and others 1993; Holmes and others 1990). Monkeys immunocompromised by experimental retrovirus infection are more likely to become B virus shedders. The B virus is the most challenging infection to eliminate from an SPF population; however, since the method of B virus transmission is similar to that of the retroviruses, it seemed prudent to include B virus in the SPF definition of these production colonies.
It may be as important to understand which agents are not targeted in these populations as it is to understand which are targeted (Kalter and Heberling 1990). This national nonhuman primate resource is SPF for four chosen pathogens. The 4 viral agents included in the SPF definition are: simian immunodeficiency virus (SIV), simian retroviruses 1-5 (SRV), simian T lymphotropic virus (STLV), and herpes B. Our SPF definition does not include the more ubiquitous or poorly defined viral flora of nonhuman primates (foamy viruses, adenoviruses, other herpes viruses, reoviruses, spongiform viruses) or blood parasites. These primates are not germfree, virus-antibody-free, or gnotobiotic animals. Although these SPF populations were initiated to enhance AIDS research, they are suitable for numerous other experimental applications.
Six geographically dispersed institutions successfully competed for cooperative agreement grants to develop these SPF breeding colonies. They included the University of Texas M.D. Anderson Cancer Center (UTMDACC), Science Park in Bastrop, Texas; the Laboratory Animal Breeders and Services, Inc. (LABS) in Yamassee, South Carolina; the Texas Primate Center, Hazelton Research Products, Inc. (HRP) in Alice, Texas; the University of Miami, School of Medicine, Division of Veterinary Resources in Miami, Florida; the Harvard Medical School, New England Regional Primate Research Center (NERPRC) in Southborough, Massachusetts; and the Department of Public Health (MDPH) in Lansing, Michigan. Each of the institutional and research grant program directors along with the NCRR project officer holds a position on a program management committee that coordinates, reviews, and directs the program as a national resource.
Each of the 6 institutions that successfully competed for these grants elected to develop their program using different strategies of housing, social enrichment, genetic surveillance, and breeding, but the general strategy for each has been one of using intensified viral screening methods to select, cull, maintain, and protect a nucleus breeding colony (Schapiro and others 1994; Schapiro and Bloomsmith 1995). Employing the most advanced technologies for viral screening and intensely culling positive and suspect animals have been the common threads within the national program (Lerche and others 1994; Ward and Hilliard 1994). When the SPF breeding population has been established with the necessary preventive health care, husbandry, management, and housing, reintroduction of the pathogens must be prevented as a matter of policy. Because none of the targeted viral agents occur in anything but monkeys, the SPF breeding nucleus can be adequately protected by closing the colony, that is, not adding any new animals to the population. Replacement breeders must be selected from colony offspring.
By early 1994, NIH's SPF rhesus monkey population numbered 2,078 individuals. Twenty-four percent (24%) of this population were adult females and 7% were adult males. Breeding colony statistics have been carefully defined by the program management committee, and comparative data have been collected from all of the program participants. Reviewing this data is beyond the scope of this article. Simulations of demographic composition and growth of these colonies have been developed based upon experiential assumptions concerning population growth, reproduction, mortality, and the anticipated number of animals needed by the biomedical research community. The demographic simulation indicated 150 yearling SPF monkeys would be available for research in 1994, with that number increasing to more than 550 in the calendar year 1997. By the year 2000, the combined capability of the six institutions will allow the production of more than 800 yearling SPF monkeys on an annual basis (Mehlman 1994).
We will proceed with a more detailed description of only one of the participants in this national program. The University of Texas M. D. Anderson Cancer Center's Science Park facility in Bastrop, Texas, adopted a derivation strategy to convert a conventional population of physically, behaviorally, and reproductively healthy rhesus monkeys to an SPF population. The conventional breeding colony had been established for 14 years and had operated as a closed colony since 1985. Animals were managed in breeding harems of 1 male and 7 or 8 females in outdoor holding buildings or corncribs. The physical facilities and outdoor site characteristics provided the flexibility needed to accomplish the SPF derivation strategy. The prefabricated aluminum panels of the outdoor holding buildings could be selectively assembled to house animals in social harem groups, peer groups, or to hold racks of animals housed singly or in pairs. Implementation of the SPF program was performed by an experienced, trained, and dedicated staff.
METHODS
The original conventional colony underwent intense viral screening. The monkeys were separated into new breeding harems based upon their viral status, and the harems were managed as separate populations until the nucleus of a true SPF production colony could be established. In addition to separating the animals according to their viral profiles, the derivation criteria also included parentage and lifetime housing history. Of the 286 rhesus monkeys that were initially dedicated to this program, 172 were proven breeders (145 females, 27 males), 73 were replacement breeders, and 41 were yearlings. To satisfy all stated goals of disease and genetic monitoring and provide a breeding plan that maximized animal well-being and safety, a programmatic consortium was designed with collaborative subcontracts and consultantships.
Our derivation strategy involved intense, long-term, serological viral screening, along with stringent exclusion of animals that were positive or suspected to be positive for B virus and the targeted retroviruses. Exclusion of animals was accomplished first through noncontact and then limited-contact housing. We were confident this strategy would result in the establishment of the desired SPF population (Weigler and others 1990; Lerche and others 199 I). Several precautions were taken to avoid cross-contamination among virus-negative, virus-positive, and indeterminate populations: separate equipment was used for each population; in the cases where there was common equipment and facilities, these were carefully disinfected; and trained personnel wore color-coded clothing and followed strict traffic patterns and rigid standard operating procedures. The disease eradication focus was tempered with compatible programs and policies developed by behavioral psychologists to address the need to produce reproductively and behaviorally competent offspring reared in an enriched environment (Schapiro and Bloom-smith 1995). To reduce the risks associated with latent viruses and with animals harboring viruses with no antibody response, serological screening had to be frequent, repetitive over time, and employ numerous testing techniques (Sauber and others 1992). Serological screening included titration, modified titration, and competitive ELISA tests, western blots, radioimmunoprecipitation assay (RIPA), cocultivation of the SRV virus from PBMCs, and polymerase chain reaction (PCR) (Lerche and others 1994; Ward and Hilliard 1994). There are several publications that describe our exclusionary list of pathogens and the techniques used in detecting them (Tsai and others 1989; Lairmore and others 1990; Lerche and others 1991, 1994; Roberts 1991; Scincariello and others 1993; Ward and Hilliard 1994).
Initial screening of the conventional population indicated the incidence of B virus to be 46%, considered typical of most conventional rhesus breeding colonies. The incidence of B virus in mother-reared infants less than 1 year old was only 14%. Serological surveys for simian retroviruses indicated no incidence of SRV or SIV in this population. The animals that had indeterminate SRV status were screened by virus isolation techniques. The incidence of STLV in the population was 6.2%, and all STLV positive animals were 4 years old and older.
Figure 1 illustrates the overall derivation strategy and timeline. Table 1 provides the definition of the group nomenclature used in Figure 1. After our initial screening of 400 rhesus monkeys there were only a few serologically B virus-negative animals. All serologically B virus-negative and retrovirus-negative animals were reorganized into new breeding harem groups with proven male and female breeders. The majority of our breeding colony was serologically B virus-positive and retrovirus-negative. Offspring of the B virus-positive population were put through the derivation strategy. The infants were mother-reared for I year. They were then weaned and housed singly for 1 year, during which time a detailed environmental enrichment program was employed. (Schapiro and others 1994). At 2 years of age, the animals were housed in pairs; at 3 years, they were put into peer groups; and at 4 years, breeding harems were created. All animals were tested every 2 months for B virus and every 4 months for retroviruses from the time they were 6 months old (1989), until 1992. The viral screening schedule is listed in Table 2. All animals demonstrating seroconversion or having indeterminate status were marketed as conventional animals. Their cagemates were kept in separate groups and retested; these animals were either kept in the program or marketed as conventional animals, depending on the results of follow-up testing.
Dr. Julia Hilliard of the Southwest Foundation for Biomedical Research in San Antonio, Texas, provided all B virus surveillance testing. Dr. Nicholas Lerche of the California Regional Primate Research Center in Davis, California provided all simian retrovirus surveillance testing and virus isolation until July 1992. Since then, Dr. Tahir Rizvi, Section of Experimental Pathology, UTMDACC, has provided retroviral surveillance testing and outside laboratory quality assurance confirmation testing for the colony. Dr. William Stone of Trinity University in San Antonio, Texas, has provided all genetic monitoring, which yielded practical colony management data such as kinship coefficients, average heterozygosity, inbreeding coefficients, and effective population size. Each animal's genetic value to the colony is reviewed prior to animal sales and replacement breeder selection. There is published information concerning the results of monitoring this national resource of SPF nonhuman primates (Manis and others 1993; Ely and others 1994; Lerche and others 1994; Ward and Hilliard 1994).
RESULTS
By 1993, we had established a population that was serologically negative for all of the agents included in our SPF definition. We continued to monitor the colony for all targeted agents but at a reduced frequency; B virus surveillance was semiannual and simian retrovirus surveillance was performed annually. Occasional B virus seroconversions have occurred but all have been in animals that had some contact with B virus-positive animals at some point in their lives. There have been no B virus seroconversions in offspring of B virus-negative animals. We will continue our selective breeding of B1, B2D, B2N and B1N subpopulations. While these subpopulations are lifetime seronegative, they do not meet our true SPF criteria, which include having serologically negative parentage and B virus-negative lifetime housing history. The B1N1 and B2D1 animals will qualify as true SPF animals. The first of these were born in 1992.
The number of SPF animals we have been able to generate has exceeded our original projections. This information along with an explanation of how these figures were calculated is listed in Table 3. Relevant breeding colony statistics for the Bastrop colony are presented in Table 4. These statistics have varied considerably as the population was redistributed by viral status, while new social groups (harems) were formed, and the transition to young, inexperienced breeders that met our SPF criteria took place. We anticipate these production statistics will eventually return to the pre-SPF-transition values.
DISCUSSION
Limited definition (B virus, SIV, SRV, STLV) SPF rhesus monkey breeding colonies are achievable and can become cost-effective. Because it is labor intensive, the start-up costs for an SPF program are high, but once the SPF nucleus population is established, the characteristics of the selected viruses and their method of transmission should allow us to eventually return to the more conventional and cost-effective management practices.
The derivation strategy adopted by the Bastrop team has proven successful and may represent a model for other laboratories to consider. Our derivated offspring have demonstrated good breeding and parenting skills (Schapiro and others 1994). Our breeding strategy, which includes maintaining socially compatible breeding harems (7 to 8 adults) with mother-reared infants, is cost-effective, satisfies the animals' need for a socially enriched environment, and significantly enhances the long-term propagation potential of this population. Small group, or social, housing also makes a significant contribution to effective disease surveillance. The latent potential of B virus and the possibility that an occasional animal could harbor one of these viruses without eliciting a detectable immune response (false negative) is a major weaknesses in a seroconversion-based surveillance program (Sauber and others 1992). Group housing, however, provides a built-in sentinel program. If a nonresponsive or latently infected (false negative) animal eludes all of our technical surveillance, it would eventually be detected by seroconversion of one of the companion animals. This is a reassuring fringe benefit of small group (social) housing. The high costs associated with an SPF colony start-up have necessitated high prices for SPF rhesus monkeys--S2500 to $3000 is the average cost of a 2-year-old animal. Once our SPF populations are established, we anticipate replacing the intense surveillance, husbandry, and population management procedures with more conventional approaches. At that point, animal management, health care, and husbandry requirements will not differ significantly from a closed, conventional, domestic breeding colony. This should make it possible to produce superior quality monkey models at costs comparable to today's conventional colonies. The characteristics and method of transmission of the viruses we have eliminated from our SPF colonies should allow us to protect the SPF status in the long-term by simply not introducing diseased monkeys.
In conclusion, domestic SPF nonhuman primate breeding colonies should be the trend of the future. Veterinary scientists have an obligation to see that the quality of the animal models used in research keeps pace with the rapidly advancing technologies of molecular research. The foresight of NCRR in financially seeding this innovative program should be commended.
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TABLE 1 Standardized Nomenclature for Rhesus SPF Derivation Program
B = breeding animal; 1 = retro(-) B virus(-) | B -- breeding animal; 1: retro(-) B virus(+) | ||
| B1 | Conventional breeders that were negative (-) for retroviruses and herpes B virus (-) on initial survey but had herpes B virus (+) parents or have historically been housed with Herpes B virus (+) companions; will eventually be marketed | B2 | Conventional breeders that were indeterminates or positive (+) for retroviruses and herpes B virus (+) on initial survey; will eventually be marketed |
N = nonderivation strategy; SPF = true SPF animals | D -- derivation strategy; N: nonderivation strategy; SPF -- true SPF animals | ||
| B1N | Offspring that are negative (-) for retroviruses and herpes B virus but were peer-housed since weaning rather than going through the derivation strategy | B2D | Offspring that are negative (-) for retroviruses and herpes B virus and were put through the derivation strategy |
| B1N1 | Offspring of B1N; greatest potential for being SPF based on parentage and management history | B2N | Offspring that are negative (-) for retroviruses and herpes B virus but were peer-housed since weaning rather than going through the derivation strategy; may eventually be marketed |
| B2N1 | Offspring of nonderivation offspring | ||
| B2D1 | Offspring of derivation offspring; greatest potential for being SPF based on parentage and management history; first B2D1 born 04/04/92. | ||
TABLE 2 Testing Schedule for Viruses
| 1989 | ||||||||||||||
| 1990 | ||||||||||||||
| 1991 | ||||||||||||||
| 1992 | ||||||||||||||
| 1993 | ||||||||||||||
| 1994 | ||||||||||||||
| 1995 | ||||||||||||||
| 1996 | ||||||||||||||
+ herpes virus B testing
¨ retroviruses testing SIV, STLV, SRV
Testing schedule
a - initial screen
b - 2 months
c - 4 months
d - 6 months
e - annually
Age differential
* less than 5 years
+ over 5 years of age
TABLE 3 Projected vs. Actual SPF Animals
| Animal age (yrs) | Projected SPF animals* | Actual SPF animals* |
| 7 | 14 | 40 |
| 6 | 14 | 49 |
| 5 | 14 | 48 |
| 4 | 15 | 30 |
| 3 | 21 | 58 |
| 2 | 42 | 41 |
| 1 | 106 | 67 |
| TOTAL | 226 | 333 |
SPF projections based on 123 births per year and B virus seroconversion. (e.g., births/year x Bv serconversions = projected SPF animals; for 1-year-old animals: 123 x 0.14 = 106; for 2-year-old animals; 106 x.60 = 64, 106- 64 = 42 )
| Age in years | B virus seroconversions |
| 0-1 | 14% |
| 1-2 | 60% |
| 2-3 | 50% |
| 3-4 | 30% |
| 4-5 | 10% |
| 5-6 | 0% |
TABLE 4 Seven Year Summary of SP/DVS Rhesus Breeding colony Production
| Production data | 1988 | 1989 | 1990 | 1991 | 1992 | 1993 | 1994 |
| Pregnancy rate | 84% | 63% | 57% | 86% | 88% | 79% | 80% |
| Production rate | 79% | 56% | 47% | 81% | 76% | 70% | 71% |
| Live birth rate | 81% | 58% | 52% | 81% | 80% | 71% | 77% |
| Survival rate (to 1 year of age) | 97% | 89% | 91% | 95% | 92% | 93% | 91% |
| Pregnancy rate: | number of pregnant females (live births + fetal deaths)/number of productive females |
| Live birth rate: | number of live births/number of productive females |
| Production rate: | (number of live births--number of neonatal deaths)/number of productive females |
| 1 -year survival rate: | number of infants reaching one year of age/number of live births |
FIGURE 1 The overall derivation strategy and timeline for a colony of SPF rhesus monkeys. Definitions of the group nomenclature are provided in Table 1.
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