Polyomaviruses of Nonhuman Primates: Implications for Research

Polyomaviruses are a family of small nonenveloped DNA viruses that infect birds and mammals. At least 7 nonhuman primate polyomaviruses that occur in macaques, African green monkeys, marmosets baboons, and chimpanzees have been described, as well as 4 polyomaviruses that occur in humans. Simian virus 40 (SV40), which infects macaques, was the first nonhuman primate polyomavirus identified as a contaminant of early polio vaccines. Primate polyomaviruses cause inapparent primary infections but persist in the host and can cause severe disease in situations of immunocompromise. This review describes the primate polyomaviruses, and the diseases associated with the viruses of macaques. In macaques, the greatest current concerns are the potential confounding of study results by polyomavirus infections and the zoonotic potential of SV40.Abbreviations: PML, progressive multifocal leukoencephalopathy; SV40, Simian virus 40Polyomaviruses were previously members of the family Papovaviridae, which included (and derived its name from) rabbit papilloma virus (pa), mouse polyoma virus (po), and simian vacuolating virus (va). Papovaviruses are nonenveloped viruses, with double-stranded circular DNA and an icosahedral capsule. Since the 1980s, studies of Simian virus 40 (SV40) and mouse polyomavirus have demonstrated that these viruses have smaller capsids (45 nm versus 50 nm), smaller genomes (5 kb versus 8 kb), and a different genomic organization than those of papillomaviruses. SV40 and mouse polyomavirus now form an independent family, Polyomaviridae.¹⁸More than 13 members of Polyomaviridae infect mammals and birds. The first polyomavirus was discovered in 1953 in mice²⁸ and was so named because it caused tumors at multiple sites in neonatal mice. Indeed oncogenicity is a common feature of polyomaviruses, particularly tumor production in non-native hosts. Various members of the group transform cell lines and immortalize primary cell cultures as well as induce tumors in susceptible animals. SV40 was identified in 1960 in primary macaque kidney cell cultures, as a contaminant of polio vaccines.⁶⁸ In 1971, the human polyomaviruses BKV²³ and JCV⁵⁴ were identified (both are named after the initials of the patients in which they were first recognized). JCV was discovered in the brain of a patient with progressive multifocal leukoencephalopathy, and BKV was found in the urine of a renal transplant patient. Recently, 2 additional polyomaviruses of the nasopharynx of humans, KIV and WUV, have been identified^2,25 through the use of molecular techniques. KIV was found in nasopharyngeal samples from patients with respiratory disease, and WUV initially was detected in a child with pneumonia. KIV and WUV are closely related genetically and may form a new subfamily of polyomaviruses: their early coding regions (T antigens) are similar to those of other primate polyomaviruses, but their late regions (structural proteins) differ.^7,25 Both KIV and WUV appear to be geographically widespread.The capsids of the polyomaviruses contain 3 structural proteins: VP1, the major capsid protein, and VP2 and VP3, which enclose a single molecule of viral DNA. The viruses also encode regulatory proteins, the T (tumor) antigens. SV40 and other primate polyomaviruses encode 2 T antigens, large T and small t, whereas mouse polyomavirus and some of the other family members have a third, middle T antigen. The T antigens of SV40, BKV, and JCV have about 75% amino-acid homology.⁵⁸ The T antigen of SV40 is essential for initiation of viral DNA replication and promotes transformation and immortalization of host cells, partially through binding to and inhibiting tumor suppressor proteins p53, p107, p130 (pRb2), and pRb (reviewed in reference 10).     

Evolution of Multilevel Social Systems in Nonhuman Primates and Humans

Multilevel (or modular) societies are a distinct type of primate social system whose key features are single-male–multifemale, core units nested within larger social bands. They are not equivalent to fission–fusion societies, with the latter referring to routine variability in associations, either on an individual or subunit level. The purpose of this review is to characterize and operationalize multilevel societies and to outline their putative evolutionary origins. Multilevel societies are prevalent in three primate clades: papionins, Asian colobines, and hominins. For each clade, we portray the most parsimonious phylogenetic pathway leading to a modular system and then review and discuss likely socioecological conditions promoting the establishment and maintenance of these societies. The multilevel system in colobines (most notably Rhinopithecus and Nasalis) has likely evolved as single-male harem systems coalesced, whereas the multilevel system of papionins (Papio hamadryas, Theropithecus gelada) and hominins most likely arose as multimale–multifemale groups split into smaller units. We hypothesize that, although ecological conditions acted as preconditions for the origin of multilevel systems in all three clades, a potentially important catalyst was intraspecific social threat, predominantly bachelor threat in colobines and female coercion/infanticide in papionins and humans. We emphasize that female transfers within bands or genetic relationships among leader males help to maintain modular societies by facilitating interunit tolerance. We still lack a good or even basic understanding of many facets of multilevel sociality. Key remaining questions are how the genetic structure of a multilevel society matches the observed social effort of its members, to what degree cooperation of males of different units is manifest and contributes to band cohesion, and how group coordination, communication, and decision making are achieved. Affiliative and cooperative interunit relations are a hallmark of human societies, and studying the precursors of intergroup pacification in other multilevel primates may provide insights into the evolution of human uniqueness.     

Lesions of the Precentral Gyrus in Nonhuman Primates: A Pre-Medline Bibliography

Many contemporary investigators are unaware of the important papers involving lesions of the primate primary motor cortex published prior to those revealed by a computer search of the literature (i.e., papers published prior to about 1966). In order to increase awareness of these reports, we present here an annotated bibliography of these papers beginning with that of Ferrier and Yeo (1884). We provide evidence that these papers can provide valuable information on the function of the primate motor cortex and on recovery of behavior after brain lesions, and are also useful for sharpening the questions posed by more refined modern studies.     

Comparisons of Intraunit Relationships in Nonhuman Primates Living in Multilevel Social Systems

Multilevel social systems have evolved in several species of cercopithecoid primates and appear to be an effective means of changing group size amid variation in environmental conditions. Larger groupings of these species fission and fuse, making intraunit relationships essential to maintain the integrity of the smallest social units. We examine these intraunit relationships in four primates with multilevel social systems: proboscis monkeys (Nasalis larvatus), snub-nosed monkeys (Rhinopithecus roxellana), hamadryas baboons (Papio hamadryas), and geladas (Theropithecus gelada), using social network analysis. The proboscis monkeys and hamadryas baboons were wild and unprovisioned, whereas the snub-nosed monkeys and geladas were partly provisioned. Comparison of eigenvector centrality coefficients revealed a phylogenetic difference in the key individuals maintaining social networks between the colobines and the cercopithecines: females were more central in proboscis and snub-nosed monkeys, with males generally peripheral to social interaction, whereas males were more central than females in geladas and hamadryas. A comparison of sex differences in clustering coefficients, however, revealed a significant difference only in geladas, suggesting that one-male–multifemale units in this species become more unstable when females, but not males, are removed from social networks. Taken together, our results reveal the strongest differences between geladas, characterized by female philopatry and male dispersal, and the three species with bisexual dispersal. These results demonstrate the potential for social network analysis to reveal the social bonds most important for maintaining cohesion of the smallest units of primate multilevel societies. This, in turn, can serve as a proxy, in the absence of long-term data, for underlying patterns of sex-biased dispersal and philopatry.     

Blood Collection Procedure of Laboratory Primates: A Neglected Variable in Biomedical Research

A survey of 75 biomedical articles dealing with stress-dependent blood parameters in caged primates revealed that the conditions under which blood collection occurred were in most cases described either not at all or so haphazardly that it would be impossible to determine if humane handling procedures were used and basic principles of scientific methodology applied. These findings were unexpected because there is ample scientific evidence not only that stress-sensitive research data are influenced by traditional blood sampling procedures, but also that those data-biasing effects can be avoided. If dependent variables of the blood collection procedure are not controlled, data variability will increase, automatically increasing the number of animals needed for statistical analysis. For ethical and scientific reasons, it was recommended that editors of biomedical journals require authors to provide sufficient information of the blood collection--and, when applicable, the sedative injection--procedure to ensure that the experiment was done with the smallest number of animals possible to achieve statistical significance and that the investigation can be replicated reliably in another laboratory and the research data interpreted with reasonable accuracy.     

Training Nonhuman Primates to Cooperate With Scientific Procedures in Applied Biomedical Research

This report provides a brief overview of aspects of training nonhuman primates who have been, and continue to be, used in this laboratory. The research context involves applied behavioral studies in which animals are trained to perform complex operant behavioral sequences, often in their homecage environment. In such studies, animals have freedom to choose whether to engage in appetitively reinforced behavioral tests that employ neither food deprivation nor fluid management. This background of operant conditioning has provided an insight to, and a context for, animal training both as an adjunct to general laboratory management and as a way to expedite scientific procedures. Thus, training has potential implications for both well-being and scientific quality, although it must be considered an adjunct to the provision of socialization with conspecifics in high quality diverse housing systems and not as an alternative to such provision. The importance of discussion and consideration of alternative procedures cannot be overemphasized.     

Noise-Induced Frequency Modifications of Tamarin Vocalizations: Implications for Noise Compensation in Nonhuman Primates

Previous research suggests that nonhuman primates have limited flexibility in the frequency content of their vocalizations, particularly when compared to human speech. Consistent with this notion, several nonhuman primate species have demonstrated noise-induced changes in call amplitude and duration, with no evidence of changes to spectral content. This experiment used broad- and narrow-band noise playbacks to investigate the vocal control of two call types produced by cotton-top tamarins (Saguinus Oedipus). In ‘combination long calls’ (CLCs), peak fundamental frequency and the distribution of energy between low and high frequency harmonics (spectral tilt) changed in response to increased noise amplitude and bandwidth. In chirps, peak and maximum components of the fundamental frequency increased with increasing noise level, with no changes to spectral tilt. Other modifications included the Lombard effect and increases in chirp duration. These results provide the first evidence for noise-induced frequency changes in nonhuman primate vocalizations and suggest that future investigations of vocal plasticity in primates should include spectral parameters.     

Abstract Knowledge in the Broken-String Problem: Evidence from Nonhuman Primates and Pre-Schoolers

There is still large controversy about whether abstract knowledge of physical problems is uniquely human. We presented 9 capuchin monkeys, 6 bonobos, 6 chimpanzees and 48 children with two versions of a broken-string problem. In the standard condition, participants had to choose between an intact and a broken string as means to a reward. In the critical condition, the functional parts of the strings were covered up and replaced by perceptually similar, but non-functional cues. Apes, monkeys and young children performed significantly better in the standard condition in which the cues played a functional role, indicating knowledge of the functional properties involved. Moreover, a control experiment with chimpanzees and young children ruled out that this difference in performance could be accounted for by differences of perceptual feedback in the two conditions. We suggest that, similar to humans, nonhuman primates partly rely on abstract concepts in physical problem-solving.     

Temporal Evolution of Ischemic Lesions in Nonhuman Primates: A Diffusion and Perfusion MRI Study

MethodsPermanent MCA occlusion was induced with silk sutures through an interventional approach via the femoral artery in adult rhesus monkeys (n = 8, 10–21 years old). The stroke lesions were examined with high-resolution DWI and perfusion MRI, and T2-weighted imaging (T2W) on a clinical 3T scanner at 1–6, 48, and 96 hours post occlusion and validated with H&E staining.ResultsThe stroke infarct evolved via a natural logarithmic pattern with the mean infarct growth rate = 1.38 ± 1.32 ml per logarithmic time scale (hours) (n = 7) in the hyperacute phase (1–6 hours). The mean infarct volume after 6 hours post occlusion was 3.6±2.8 ml (n = 7, by DWI) and increased to 3.9±2.9 ml (n = 5, by T2W) after 48 hours, and to 4.7±2.2ml (n = 3, by T2W) after 96 hours post occlusion. The infarct volumes predicted by the natural logarithmic function were correlated significantly with the T2W-derived lesion volumes (n = 5, r = 0.92, p = 0.01) at 48 hours post occlusion. The final infarct volumes derived from T2W were correlated significantly with those from H&E staining (r = 0.999, p < 0.0001, n = 4). In addition, the diffusion-perfusion mismatch was visible generally at 6 hours but nearly diminished at 48 hours post occlusion.ConclusionThe infarct evolution follows a natural logarithmic pattern in the hyperacute phase of stroke. The logarithmic pattern of evolution could last up to 48 hours after stroke onset and may be used to predict the infarct volume growth during the acute phase of ischemic stroke. The nonhuman primate model, MRI protocols, and post data processing strategy may provide an excellent platform for characterizing the evolution of acute stroke lesion in mechanistic studies and therapeutic interventions of stroke disease.     

The Origins of Language: What Nonhuman Primates Can Tell Us

The Origins of Language: What Nonhuman Primates Can Tell Us. Barbara J. King. ed. Santa Fe, NM: School of American Research, 1999. 442 pp.     

Prenatal Androgen Effects as a Proximate Mechanism Underpinning Variation in Social Behavior Among Female Nonhuman Primates

International Journal of Primatology - While the role of ecological factors in shaping primate social systems has been a central focus for decades, less attention has been given to phylogenetic...     

A Method to Determine When Active Translocation of Nonhuman Primates Is Justified

This article addresses translocation, or artificial dispersal, the movement of one or more organisms from one location to another, and focuses on the decisions to be made before translocation begins. Scientific, economic, or pragmatic reasons such as pest removal or conservation of biodiversity may account for undertaking translocation. When is translocation ethical, and how can that decision be determined? This article provides one quantitative and utilitarian method for evaluating these questions. Although this analysis may apply to any nonhuman species for which costs and benefits can be assessed, the examples in this article derive from the nonhuman primate literature.     

Alopecia: Possible Causes and Treatments, Particularly in Captive Nonhuman Primates

Alopecia (hair loss) occurs in some nonhuman primates housed in captivity and is of concern to colony managers and veterinarians. Here we review the characteristics, potential causes, and treatments for this condition. Although we focus on nonhuman primates, relevant research on other mammalian species is discussed also, due to the relative paucity of studies on alopecia in the primate literature. We first discuss the cycle of hair growth and explain how this cycle can be disrupted to produce alopecia. Numerous factors may be related to hair loss and range from naturally occurring processes (for example, seasonality, aging) to various biologic dysfunctions, including vitamin and mineral imbalances, endocrine disorders, immunologic diseases, and genetic mutations. We also address bacterial and fungal infections, infestation by parasites, and atopic dermatitis as possible causes of alopecia. Finally, we examine the role of psychogenic factors, such as stress. Depending on the presumed cause of the hair loss, various treatment strategies can be pursued. Alopecia in nonhuman primates is a multifaceted disorder with many potential sources. For this reason, appropriate testing for various disease conditions should be completed before alopecia is considered to be related to stress.Abbreviations: VDR, vitamin D receptorHair loss (alopecia) is a complex phenomenon that is not fully understood either in human or nonhuman primates. Hair loss can occur as the result of a congenital or genetic disorder, or it can develop during the lifetime of the animal. Hair loss occurring throughout life can be further divided into inflammatory and noninflammatory types. In this article, we focus on alopecia in nonhuman primates. We also will refer to humans and other mammals, given that mechanisms of hair loss and potential treatments for this disorder have been studied infrequently in nonhuman primates.Patterns of hair loss can be categorized in various ways, and several different types of scoring systems have been developed for both animals and humans.^44,45,77 Most of these systems focus either on hair volume (referring to the number of hairs per unit area and often estimated along a 3- to 5-point scale) or distribution (referring to the size and location of bald patches) or some combination of both. Using rhesus monkeys as an example, typical patterns of hair loss include: 1) substantial whole-body hair loss (balding on the head, back, legs, and arms); 2) substantial hair thinning in various body regions (that is, hair is present but sparse); 3) extensive patches of bare skin, often bilateral in presentation, interspersed with normal hair; and 4) 1 or 2 small patches of bare skin on normally haired monkeys. A third dimension of hair loss is duration: hair loss can be short-term (less than 3 mo), long-term (lasting anywhere from 3 to 24 mo), or permanent. In the following paragraphs, we consider the typical hair cycle and various factors that can disrupt this cycle to cause loss of hair.     

A Two-Antibody Pan-Ebolavirus Cocktail Confers Broad Therapeutic Protection in Ferrets and Nonhuman Primates

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Epidemiology of Invasive Klebsiella pneumoniae with Hypermucoviscosity Phenotype in a Research Colony of Nonhuman Primates

Invasive Klebsiella pneumoniae with hypermucoviscosity phenotype (HMV K. pneumoniae) is an emerging human pathogen that, over the past 20 y, has resulted in a distinct clinical syndrome characterized by pyogenic liver abscesses sometimes complicated by bacteremia, meningitis, and endophthalmitis. Infections occur predominantly in Taiwan and other Asian countries, but HMV K. pneumoniae is considered an emerging infectious disease in the United States and other Western countries. In 2005, fatal multisystemic disease was attributed to HMV K. pneumoniae in African green monkeys (AGM) at our institution. After identification of a cluster of subclinically infected macaques in March and April 2008, screening of all colony nonhuman primates by oropharyngeal and rectal culture revealed 19 subclinically infected rhesus and cynomolgus macaques. PCR testing for 2 genes associated with HMV K. pneumoniae, rmpA and magA, suggested genetic variability in the samples. Random amplified polymorphic DNA analysis on a subset of clinical isolates confirmed a high degree of genetic diversity between the samples. Environmental testing did not reveal evidence of aerosol or droplet transmission of the organism in housing areas. Further research is needed to characterize HMV K. pneumoniae, particularly with regard to genetic differences among bacterial strains and their relationship to human disease and to the apparent susceptibility of AGM to this organism.Abbreviations: AGM, African green monkey; HMV K. pneumoniae, invasive Klebsiella pneumoniae with hypermucoviscosity phenotype; NHP, nonhuman primate; RAPD, random amplification of polymorphic DNAKlebsiella pneumoniae is an enteric, gram-negative, lactose-fermenting bacillus with a prominent capsule. This bacterium has been associated with peritonitis, septicemia, pneumonia, and meningitis in both Old and New World primates,^10,13,29 although it also is reported to constitute normal fecal and oral flora in many nonhuman primates (NHP).¹² Pathogenic strains associated with the upper respiratory tract typically are heavily encapsulated.¹² Over the past several decades, human medical literature indicates the emergence of an invasive K. pneumoniae disease in Taiwan and other Asian countries, in which community-acquired pyogenic liver abscesses have been attributed to strains of invasive K. pneumoniae with a unique hypermucoviscous phenotype (HMV K. pneumoniae).^{6,17-19,21,26,34} The hypermucoviscous phenotype has also been associated with other serious complications, including bacteremia, meningitis, and endophthalmitis. This strain of Klebsiella has become an emerging cause of pyogenic liver abscesses in some nonAsian countries, including the United States.^16,20,36,39 The majority of clinical cases of HMV K. pneumoniae are in the Asian population, particularly in patients with diabetes mellitus.^3,4,33 Determination of the HMV phenotype typically is based on a positive string test.^8,35,39Several virulence factors have been associated with HMV K. pneumoniae. Klebsiella spp. generally develop prominent polysaccharide capsules which increase virulence by protecting the bacteria from phagocytosis and preventing destruction by bactericidal serum factors. Capsular serotypes K1 or K2 have been reported as the major virulence determinants for human HMV K. pneumoniae liver abscesses.^5,8,37,38 In addition, the mucoviscosity-associated gene magA, which encodes a structural outer membrane protein of the K1 serotype, and rmpA (regulator of the mucoid phenotype gene; located on a plasmid) have been proposed as virulence factors.^{9,27,31,40,41} Recently, it was suggested that 2 clones, CC23 ^K1 and CC82^K1, are strongly associated with primary liver abscess and respiratory infection, respectively.²Over a period of several months in 2005 to 2006, 7 African green monkeys (AGM; Chlorocebus aethiops) in the US Army Medical Research Institute of Infectious Diseases research colony developed abscesses in multiple locations and either died or were euthanized when the abscesses were determined to be nonresectable.³⁵ HMV K. pneumoniae of the K2 serotype and carrying rmpA was determined to be the cause of the infection in 1 case, and the 6 other cases had similar clinical and pathologic features. This report³⁵ is the only documentation, to our knowledge, of natural infection with HMV K. pneumoniae in NHP. As a result of these cases, the US Army Medical Research Institute of Infectious Diseases instituted policies to exclude HMV K. pneumoniae from the colony. The organism was included as a specific pathogen-free requirement for vendors, and K. pneumoniae culture results were reported during quarantine periods and on routine semiannual examination for all colony NHP.