Nonhuman Primates in Biomedical Research: Diseases

American College of Laboratory Animal Medicine Series

Steven H. Weisbroth, Ronald E. Flatt, and Alan L. Kraus, eds.:

The Biology of the Laboratory Rabbit, 1974

Joseph E. Wagner and Patrick J. Manning, eds.:

The Biology of the Guinea Pig, 1976

Edwin J. Andrews, Billy C. Ward, and Norman H. Altman, eds.:

Spontaneous Animal Models of Human Disease, Volume 1, 1979; Volume II, 1979

Henry J. Baker, J. Russell Lindsey, and Steven H. Weisbroth, eds.:

The Laboratory Rat, Volume I: Biology and Diseases, 1979; Volume II: Research Applications, 1980

Henry L. Foster, J. David Small, and James G. Fox, eds.:

The Mouse in Biomedical Research, Volume I: History, Genetics, and Wild Mice, 1981; Volume II: Diseases, 1982; Volume Ill: Normative Biology, Immunology, and Husbandry, 1983; Volume IV: Experimental Biology and Oncology, 1982

James G. Fox, Bennett J. Cohen, and Franklin M. Loew, eds.:

Laboratory Animal Medicine, 1984

G. L. Van Hoosier, Jr., and Charles W. McPherson, eds.:

Laboratory Hamsters, 1987

Patrick J. Manning, Daniel H. Ringler, and Christian E. Newcomer, eds.:

The Biology of the Laboratory Rabbit, 2nd Edition, 1994

B. Taylor Bennett, Christian R. Abee, and Roy Henrickson, eds.:

Nonhuman Primates in Biomedical Research, Volume I: Biology and Management, 1995; Volume II: Diseases, 1998

Dennis F. Kohn, Sally K. Wixson, William J. White, and G. John Benson, eds.:

Anesthesia and Analgesia in Laboratory Animals, 1997

James G. Fox, Lynn C. Anderson, Franklin M. Loew and Fred W. Quimby, eds.:

Laboratory Animal Medicine, 2nd Edition, 2002

Mark A. Suckow, Steven H. Weisbroth and Craig L. Franklin, eds.:

The Laboratory Rat, 2nd Edition, 2006

James G. Fox, Muriel T. Davisson, Fred W. Quimby, Stephen W. Barthold, Christian E. Newcomer and Abigail L. Smith, eds.:

The Mouse in Biomedical Research, 2nd Edition, Volume I: History, Wild Mice, and Genetics, 2007; Volume II: Diseases, 2007; Volume III: Normative Biology, Husbandry, and Models, 2007; Volume IV: Immunology, 2007

Richard E. Fish, Marilyn J. Brown, Peggy J. Danneman and Alicia Z. Karas, eds.:

Anesthesia and Analgesia in Laboratory Animals, 2nd Edition, 2008

Jack R. Hessler and Noel D.M. Lehner, eds.:

Planning and Designing Animal Research Facilities, 2009

Mark A. Suckow, Karla A. Stevens, and Ronald P. Wilson, eds.:

The Laboratory Rabbit, Guinea Pig, Hamster and other Rodents, 2011

Christian R. Abee, Keith Mansfield, Suzette Tardif and Timothy Morris, eds.:

Nonhuman Primates in Biomedical Research, 2nd Edition, Volume I: Biology and Management, 2012; Volume II: Diseases, 2012

Kathryn Bayne and Patricia V. Turner, eds.:

Laboratory Animal Welfare, 2012

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Preface

Biomedical research using nonhuman primates continues to provide important insights into the pathogenesis and treatment of diseases that impact human health. In recent years, translational research has become an increasingly emphasized area in biomedical research. This emphasis on translating discoveries made in basic research into treatments that are useful to patients requires animal models that allow scientists to predict human responses. Nonhuman primates have long been recognized as important models for translational research due to their phylogenetic proximity to human beings and their similarity in responses to treatment and pathogenesis of disease when compared to patients subsequently observed in clinical trials. For these reasons, the American College of Laboratory Animal Medicine (ACLAM) recognized the need for an authoritative textbook on the biology, management, and diseases of nonhuman primates used in biomedical research.

The first edition of Nonhuman Primates in Biomedical Research was edited by B. Taylor Bennett, Christian R. Abee, and Roy V. Henrickson as part of the textbook series sponsored by the American College of Laboratory Animal Medicine. It was published in two volumes, Biology and Management (1995) and Diseases (1998). The completion of the first edition required more than 10 years to plan, develop, edit, and publish. It has served as a seminal text in the field because it provided readers with the collective knowledge of experts in veterinary medicine, laboratory animal medicine, comparative medicine, and primatology as these disciplines are applied to the care and use of nonhuman primates in biomedical research. The first edition is no longer in print and used copies have become collector’s items selling for more than the original purchase price. This provided the Publications Committee of the American College of Laboratory Animal Medicine with strong justification to approve the development of this second edition of this important text.

Planning for the second edition of Nonhuman Primates in Biomedical Research began in 2006. Although much of the information in the first edition remains useful, there have been major advances in our understanding of the biology, veterinary medical care, pathology, and research uses of nonhuman primates. Planning for the second edition began with the return of Christian Abee as an editor followed by Keith Mansfield, Suzette Tardif, and Timothy Morris as co-editors.

The editors reviewed the first edition to determine those chapters that should be repeated with careful attention to chapters that required major revisions and those that required less extensive updating. The editors agreed that the text should have a more international perspective and chapters should be added that describe research areas in which nonhuman primates play a critical role. Therefore, this second edition has added chapters that provide a more international perspective on regulatory oversight of the care and use of nonhuman primates and chapters that describe important model systems and research areas. High-resolution color images have been included in this edition that illustrate gross and microscopic lesions characteristic of diseases of nonhuman primates. Color illustrations have also been included of imaging techniques that can be used in both clinical veterinary medical care and research applications.

The editors assembled an outstanding group of chapter contributors with many chapter authors from the first edition contributing once again. Chapter manuscripts were peer reviewed by experts in the respective subject areas. The reviewers of chapters provided a very important contribution by helping to make certain that chapters were accurate and fair in their review of the subject areas. Reviewers are listed in each respective volume, but are not identified with the specific chapter they reviewed.

Nonhuman Primates in Biomedical Research 2nd edition provides a comprehensive and current review of the collective knowledge of the biology, management, diseases, and research uses of nonhuman primates. The information in these volumes will be useful to clinical veterinarians, veterinary pathologists, primate caregivers and colony managers, scientists who work with nonhuman primates, and others who wish to know more about nonhuman primates.

Chris Abee, Keith Mansfield, Suzette Tardif and Timothy Morris

Acknowledgments

There are many people deserving of recognition for their many hours of dedicated service in planning, developing, and editing Nonhuman Primates in Biomedical Research 2nd edition. The editors wish to thank Laura Zapalac and Jennifer Kurtz at the Michale E. Keeling Center for Comparative Medicine and Research of the University of Texas MD Anderson Cancer Center for the many hours they devoted to scheduling editors’ conference calls, maintaining spreadsheets that allowed the editors to follow the progress of each chapter through the arduous process of composition, chapter review, authors’ revisions, first copyedit, and finally, submission of each chapter to Elsevier. We are also grateful to Rachel Tardif for her outstanding efforts in the initial copyedit of most of the chapters. Her work allowed the editors to identify and correct mistakes in chapter manuscripts prior to final copyediting by Elsevier. The editors want to give special thanks to Mary Preap at Elsevier for her gentle pressure to keep us as close as possible to our deadlines and her timely responses to the book editors’ questions and requests. And finally, I would like to thank my co-editors, Keith Mansfield, Suzette Tardif, and Tim Morris for their tireless efforts to make certain that this second edition of Nonhuman Primates in Biomedical Research met the high standard expected of the American College of Laboratory Animal Medicine Blue Book series. The completion of this second edition was truly a team effort and a team accomplishment of the chapter contributors, the chapter reviewers, the book editors, administrative staff, and the staff at Elsevier.

Chris Abee

Reviewers

Karyn L. Armstrong Covance Research Products, Inc., Alice, TX

Lynne M. Ausmann Tufts University, Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, MA

Michael B. Ballinger Amgen, Inc., Thousand Oaks, CA

Kathryn Bayne Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International, Frederick, MD

Mollie Bloomsmith Emory University, Yerkes National Primate Research Center, Atlanta, GA

Rudolf P. Bohm Jr. Tulane University, Tulane National Primate Research Center, Covington, LA

Kathleen M. Brasky Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX

William E. Britz Jr. Britz & Company, Wheatland, WY

Hannah Buchannan-Smith University of Stirling, Psychology, School of Natural Sciences, Scotland, UK

Thomas M. Butler Retired, Fair Oaks Ranch, TX

John Capitanio University of California, Davis, Department of Psychology, Davis, CA

William Cole Retired, Lansdale, PA

Lita Drobatz GlaxoSmithKline (GSK) Pharmaceuticals, King of Prussia, PA

Bennett Dyke Retired, San Antonio, TX

Marisa Elkins St. Claire National Institutes of Health, National Institute of Allergy and Infectious Diseases, Rockville, MD

James J. Elliott Texas A&M University, Comparative Medicine Program, College Station, TX

Lynn Fairbanks University of California at Los Angeles, Semel Institute, Los Angeles, CA

John Finch Charles River Laboratories, Edinburgh, UK

John Fleagle Stony Brook University, Department of Anatomical Sciences, Stony Brook, NY

Jeffrey D. Fortman University of Illinois at Chicago, Biologic Resources Laboratory, Chicago, IL

Margaret H. Gilbert Tulane University, Tulane National Primate Research Center, Covington, LA

Colin Groves Australian National University, Canberra, ACT, Australia

Patrick W. Hanley The University of Texas MD Anderson Cancer Center, Michale E. Keeling Center for Comparative Medicine and Research, Bastrop, TX

Robert F. Hoyt National Institutes of Health, National Heart, Lung and Blood Institute, Bethesda, MD

Denis Lambrights GlaxoSmithKline (GSK) Biologicals, Rixensart, Belgium

Judy MacArthur-Clark Animals in Science Regulation Unit, Home Office, London, UK

Christopher L. Medina Abbott Laboratories, Comparative Medicine, Abbott Park, IL

Yasmina A. Paramastri Vanderbilt University Medical Center, Department of Pathology, Microbiology and Immunology, Nashville, TN

Sulli J. Popilskis New York Medical College, Department of Comparative Medicine, Valhalla, NY

Wendy Saltzman University of California at Riverside, Department of Biology, Riverside, CA

Michael Schillaci University of Toronto, Department of Anthropology, Toronto, Ontario, Canada

Mårten K.J. Schneider University Hospital of Zurich, Laboratory of Vascular Immunology, Division of Internal Medicine, Zurich, Switzerland

Mary Schneider University of Wisconsin-Madison, Departments of Kinesiology (Occupational Therapy Program) and Psychology, Madison, WI

M. Michael Swindle Medical University of South Carolina, Department of Comparative Medicine, Charleston, SC

Maureen Thompson Emory University, Yerkes National Primate Research Center, Atlanta, GA

Duane Ullrey Michigan State University, Departments of Animal Science and Fisheries & Wildlife, East Lansing, MI

Gary L. White The University of Oklahoma Health Sciences Center, Comparative Medicine, Oklahoma City, OK

Gregory K. Wilkerson The University of Texas MD Anderson Cancer Center, Michale E. Keeling Center for Comparative Medicine and Research, Bastrop, TX

Lawrence E. Williams The University of Texas MD Anderson Cancer Center, Michale E. Keeling Center for Comparative Medicine and Research, Bastrop, TX

Roman F. Wolf The University of Oklahoma Health Sciences Center, Comparative Medicine, Oklahoma City, OK

Simon Young AstraZeneca, Alderley Park, Cheshire, UK

Marcus Young Owl California State University, Long Beach, Department of Anthropology and Biological Sciences, Long Beach, CA

Contributors

John W. Barnwell, Division of Parasitic Diseases and Malaria, Centers for Disease Control & Prevention, Atlanta, GA

Joseph Bielitzki, University of Central Florida, Orlando, FL

Alan G. Brady, The University of Texas MD Anderson Cancer Center, Bastrop, TX

David W. Brammer, Animal Care Operations, University of Houston, Houston, TX

Laurie Brignolo, California National Primate Research Center, Davis, CA

Jennifer A. Cann, Wake Forest University, Winston-Salem, NC, USA

Angela A.L. Carville, New England Primate Research Center, Southborough, MA

Thomas B. Clarkson, Wake Forest School of Medicine, Department of Pathology, Section on Comparative Medicine, Winston-Salem, NC

J. Mark Cline, Wake Forest School of Medicine, Department of Pathology, Section on Comparative Medicine, Winston-Salem, NC

Mark l. Eberhard, Division of Parasitic Disease, Centers for Disease Control and Prevention, Atlanta, GA

James G. Else, Yerkes National Primate Center, Atlanta, GA

M.A. Fahey, Harvard Medical School, New England Primate Research Center, Southborough, MA

JoAnne L. Flynn, Department of Microbiology and Molecular Genetics and the Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA

Elizabeth W. Ford, The Scripps Research Institute, La Jolla, CA

Mary R. Galinski, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA

Juri G. Gelovani, The University of Texas MD Anderson Cancer Center, Houston, TX

Susan Gibson, Department of Comparative Medicine, College of Medicine, University of South Alabama, Mobile, AL

H. James Harwood Jr.., Wake Forest University, Winston-Salem, NC

Charlotte E. Hotchkiss, Washington National Primate Research Center, University of Washington, Seattle Washington

Jay R. Kaplan, Wake Forest School of Medicine, Department of Pathology, Section on Comparative Medicine, Winston-Salem, NC

Matthew J. Kessler, New England Primate Research Center, Harvard Medical School, Southborough, MA

Joshua A. Kramer, New England Primate Research Center, Harvard Medical School, Southborough, MA

Stephen M. Krause, Biomarkers and Personalized Medicine CFU Eisai Product Creation Systems, Andover, MA

Roger Lemon, UCl Institute of Neurology, National Hospital for Neurology and Neurosurgery, London

Paul C. Levesque, Department of Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Princeton, New Jersey

Philana Ling Lin, Department of Pediatrics, Division of Pediatric Infectious Disease, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA

Linda J. Lowenstine, School of Veterinary Medicine, University of California, Davis, CA

Joseph L. Mankowski, Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland

Keith Mansfield, New England Primate Research Center, Harvard Medical School, Southborough, MA

Paul J. McCracken, Biomarkers and Personalized Medicine CFU Eisai Product Creation Systems, Andover, MA

Andrew D. Miller, New England Primate Research Center, Harvard Medical School, Southborough, MA

Kent G. Osborn, University of California, San Diego, La Jolla, CA

Donna M. Platt, Harvard Medical School, New England Primate Research Center, Southborough, MA

Kenneth P.H. Pritzker, Mount Sinai Hospital/University of Toronto, Toronto, Canada

James K. Rowlett, Harvard Medical School, New England Primate Research Center, Southborough, MA

Vito G. Sasseville, Discovery Pathology, Preclinical Safety, Novartis Institutes for BioMedical Research, Inc., Cambridge, MA

Kathryn A. Shelton, Wake Forest School of Medicine, Department of Pathology, Section on Comparative Medicine, Winston-Salem, NC

Joe Simmons, Charles Rivers Laboratories, Houston, TX

Karen Strait, Yerkes National Primate Center, Atlanta, GA

Lynn Wachtman, New England Primate Research Center, Harvard Medical School, Southborough, MA

Janice D. Wagner, Wake Forest University, Winston-Salem, NC

S.V. Westmoreland, Harvard Medical School, New England Primate Research Center, Southborough, MA

Christopher T. Winkelmann, Merck Research Laboratories, West Point, PA

Li Zhang, Wake Forest University, Winston-Salem, NC

TABLE OF CONTENTS

Cover Image

Title

American College of Laboratory Animal Medicine Series

Copyright

Preface

Acknowledgments

Reviewers

Contributors

Chapter 1. Viral Diseases of Nonhuman Primates

Introduction

Enveloped DNA Viruses

Nonenveloped DNA-Containing Viruses

Enveloped RNA-Containing Viruses

Nonenveloped RNA-Containing Viruses

Chapter 2. Bacterial and Mycotic Diseases of Nonhuman Primates

Introduction

Bacterial Diseases

Mycotic Diseases

Chapter 3. Tuberculosis Research using Nonhuman Primates

Introduction

Human Tuberculosis

Pathobiology of Human Disease: Natural History of Tuberculosis

Primate Models of Tuberculosis

Pathological Features of Model

Statistical Considerations

Occupational Health and Safety Considerations: Biosafety Level 3 Pathogen

Specific Areas of Research that Benefit from the Nonhuman Primate Model of Tuberculosis

Alternative Animal Models, In Silico Models, and In Vitro Systems

Summary

Acknowledgments

Chapter 4. Parasitic Diseases of Nonhuman Primates

Introduction

Protozoan Parasites

Metazoan Parasites

Acknowledgments

Chapter 5. Nonhuman Primate Models for Human Malaria Research

Introduction

Human Malaria

Life Cycle of Primate Malaria Parasites

Clinical Malaria and Pathology

Nonhuman Primate Models of Human Malaria (Biology, Disease Pathogenesis, Immunity, and Testing of Vaccines or Drugs)

Some Methods and Considerations for Investigations of Malaria Biology and Vaccines

Chapter 6. Neoplasia and Proliferative Disorders of Nonhuman Primates

Introduction

Characterization of Neoplasia

Mechanisms of Cancer Development

System Specific Neoplasia

Treatment and Prognosis

Chapter 7. Hematopoietic, Cardiovascular, Lymphoid and Mononuclear Phagocyte Systems of Nonhuman Primates

Introduction

Hematology

The Heart and Vasculature

Lymphoid and Mononuclear Phagocyte Systems

Chapter 8. Nonhuman Primate Models of Atherosclerosis

Introduction

Pathobiology of Human Atherosclerosis

Advantages of a Nonhuman Primate Model

Introduction to Primate Models

New World Monkeys

Old World Monkeys

Summary Assessment

Acknowledgements

Chapter 9. Respiratory System Diseases of Nonhuman Primates

Introduction

Respiratory System Structure and Function

Approach to the Patient with Respiratory Disease

Upper Airway Diseases

Lower Respiratory Tract Diseases

Disorders of the Diaphragm, Pleura, and Mediastinum

Viral Diseases

Bacterial Diseases and Agents

Mycotic Diseases

Protozoan Diseases

Metazoan Parasites

Acknowledgment

Chapter 10. Urogenital System

Part A. Urinary System

Urinary System

Part B. Genital System: Female

Genital System: Female

Part C. Genital System: Male

Genital System: Male

Chapter 11. Integumentary System Diseases of Nonhuman Primates

Introduction

Structure and Function of the Skin

Definitions and Descriptions of Skin Lesions

Examination of the Skin

Diseases of the Skin

Chapter 12. Digestive System Diseases of Nonhuman Primates

Introduction

Oral Cavity

Stomach and Intestine

Liver

Exocrine Pancreas

Acknowledgments

Chapter 13. Arthritis, Muscle, Adipose Tissue, and Bone Diseases of Nonhuman Primates

Introduction

Arthritis

Connective Tissue Disorders

Skeletal Muscle Diseases

Adipose Tissue Disorders

Bone Diseases

Nutritional Disorders

Musculoskeletal Neoplasia

Acknowledgments

Chapter 14. Diabetes and Obesity Research using Nonhuman Primates

Review of Diabetes in Humans

Review of Diabetes in Nonhuman Primates

Methods for Evaluating Diabetes in Nonhuman Primates

Nonhuman Primate Models of Diabetes

Pathologic Changes in Islets in Diabetic Monkeys

Co-Morbid Conditions in Diabetes

Sex Hormones and Effects on Insulin Resistance and Diabetes

Effects of Stress, Diet, and Caloric Restriction on Insulin Resistance and Diabetes

Pharmacologic Interventions to Treat Diabetes and Obesity

Conclusions and Future Directions

Acknowledgments

Chapter 15. Nervous System Disorders of Nonhuman Primates and Research Models

Clinical and Diagnostic Approaches

Specific Procedures

Naturally Occurring Infectious Diseases

Congenital and Developmental Conditions

Age-Related Changes in the CNS

Nutritional and Metabolic Disorders

Miscellaneous Conditions

Neoplasia of the Nervous System

Important Nonhuman Primate Models of Human Neurologic Diseases

Chapter 16. Nonhuman Primate Models of the Motor System

Introduction

The Rationale for Using Nonhuman Primates in Research Focused on the Motor System

Nonhuman Primate Models and Research on the Motor System

The 3RS and Nonhuman Primate Research on the Motor System

Acknowledgments

Chapter 17. Imaging in Research Using Nonhuman Primates

Introduction

Animal Preparation

Advanced Imaging Techniques

Chapter 18. Nonhuman Primate Models of Drug and Alcohol Addiction

Introduction

The Self-Administration Model

Addiction as a Disease of the Brain

Pharmacokinetic Factors Important for Addiction Research

Behavioral Similarities Important for Addiction Research

Genetic Factors Important for Addiction Research

Conclusions

Index

Chapter 1

Viral Diseases of Nonhuman Primates

Lynn Wachtman and Keith Mansfield

New England Primate Research Center, Harvard Medical School, Southborough, MA, USA

Chapter Outline

Introduction

Enveloped DNA Viruses

Poxviridae

Monkeypox

Variola

Vaccinia

Cowpox

Yaba Monkey Tumor Virus

Yaba-Like Disease Virus

Molluscum Contagiosum

Herpesviridae

Alphaherpesvirinae

Macacine Herpesvirus 1: Herpes B Virus

Cercopithecine Herpesvirus 2: Simian Agent 8

Papiine Herpesvirus 2: Herpesvirus Papio-2 Saimiriine Herpesvirus 1: SaHV1, Herpevirus Tamarinus

Human Herpesvirus 1 and 2: HHV1 and HHV2, Herpes Simplex Virus 1 and 2

Cercopithecine Herpesvirus 9: SVV, Simian Varicella Virus

Betaherpesvirinae

Cytomegalovirus

Gammaherpesvirinae

Macacine Herpesvirus 4: RhLCV, Rhesus Lymphocryptovirus

Callitrichine Herpesvirus 3: CalHV3, Marmoset Lymphocryptovirus

Human Herpesvirus 4: EBV, Epstein-Barr Virus

Macacine Herpevirus 5: RRV, Rhesus Rhadinovirus

Retroperitoneal Fibromatosis Herpesvirus: RFHV

Ateline Herpesvirus 2 and 3 and Saimiriine Herpesvirus 2

Hepadnaviridae

Hepatitis B Virus

Nonenveloped DNA-Containing Viruses

Adenoviridae

Polyomaviridae

Polyomavirus Macacae: Simian Virus 40

Baboon Polyomavirus 1 (Polyomavirus Papionis-l; SA12)

African Green Monkey Polyomavirus (Polyomavirus Cercopitheci; Lymphotropic Papovavirus)

Polyomavirus Hominis-2 and Polymomavirus Hominis-1: JC Virus and BK Virus

Papillomaviridae

Parvoviridae

Simian Parvovirus

Enveloped RNA-Containing Viruses

Rhabdoviridae

Rabies Virus

Vesicular Stomatitis Virus

Filoviridae

Filoviruses

Orthomyxoviridae

Influenza Viruses

Paramyxoviridae

Paramyxovirinae

Parainfluenza Viruses

Measles (Rubeola) Virus

Paramyxovirus Saguinus

Pneumovirinae

Respiratory Syncytial Virus

Human Metapneumovirus

Arteriviridae

Simian Hemorrhagic Fever Virus

Togaviridae

Chikungunya Virus

Flaviviridae

Yellow Fever Virus

West Nile Virus

Kyasanur Forest Disease Virus

Dengue Viruses; Serotypes 1–4

Hepatitis C Virus (HCV)

GB Agent Viruses: GBV-A, GBV-B, and GBV-C

Arenaviridae

Lymphocytic Choriomeningitis Virus

Lassa Fever Virus

Bolivian Hemorrhagic Fever Virus: Machupo Virus

Retroviridae

Orthoretrovirinae

Simian Retrovirus (SRV)

Simian T-Cell Leukemia Virus

Other Simian T-Cell Leukemia Viruses

Simian Sarcoma Virus and Gibbon Ape Leukemia Virus

Simian Immunodeficiency Virus

Spumaretrovirinae

Simian Foamy Viruses

Nonenveloped RNA-Containing Viruses

Reoviridae

Rotavirus

Orthoreovirus

Picornaviridae

Hepatitis A Virus

Encephalomyocarditis Viruses

Simian Enteroviruses

Poliovirus

Caliciviridae

Primate Calicivirus Pan paniscus Type 1: PCV-Pan 1

Norovirus

Recovirus

Coronaviridae

Coronavirus-Like Particles

SARS Coronavirus

Hepeviridae

Hepatitis E Virus

References

Introduction

Viral infections pose a potential threat to the health of (1) laboratory and zoological colonies of nonhuman primates and (2) the personnel involved in their care. This is particularly true at facilities where there is frequent turnover or movement of animals or where animals recently imported from natural habitats are introduced into colonies of highly susceptible colony-born animals.

This chapter discusses those viral diseases of importance to captive primates or to the health of personnel involved in their care by taxonomic family to which the causative agent is classified. The rationale for this is that there is considerable overlap in the clinical and pathologic expression of diseases caused by viruses in the same taxonomic family regardless of the species affected. Obvious exceptions exist, but these will be noted.

A doctrine of comparative virology is that infection of the immunocompetent appropriate host often is associated with minimal disease, whereas infection of the inadvertent susceptible host can have devastating consequences. The likelihood of such transmission is increased when changes in the environment, either natural or imposed by humans, place different species in close proximity. An early example of this phenomenon comes from the family Herpesviridae in which infection of the natural reservoir host usually results in minimal clinical disease, whereas infection of other closely related species may result in an acutely lethal cytolytic or neoplastic process.

Because interspecies transmission of viruses may have such devastating consequences, direct contact between different nonhuman primate species should be prevented. Although isolation of primate species is the norm in well-managed modern facilities, such may not be the case with recently imported animals. Substandard separation of species, coupled with the stress of capture and movement, puts these animals at increased risk. Similarly, transmission of viral agents from nonprimate host to primate host may result in severe disease. Examples include transmission of lymphocytic choriomeningitis virus from rodents to callitrichids and the transmission of various orthopoxviruses such as monkeypox or cowpox from rodent vectors to nonhuman primates. Increasingly zoological collections have adapted multiple species exhibits and more naturalist settings. While such exhibits have many benefits, it should be remembered that they may promote inadvertent cross-species transmission of infectious agents.

Perhaps of equal importance is the realization that experimental manipulations may inadvertently expose animals to unrecognized pathogens with lethal consequences. Tissue homogenates and cell culture derivatives have transmitted simian immunodeficiency virus (SIV) and simian virus 40 in this fashion (Gormus et al., 1989; Mansfield et al., 1995). Moreover, the use of xenografts in both experimental and clinical settings is a potential route by which existing or novel pathogens may be introduced to a new population (Smith, 1993).

While infection of the natural host is often associated with minimal disease due to extensive host pathogen co-evolution, such may not be the case if the host is immunocompromised (Wachtman and Mansfield, 2008). A number of minimally pathogenic viruses may cause severe disease in animals immunosuppressed from pharmacologic manipulation or immunodeficient from concurrent infection with viruses that target the immune system. Examples of opportunistic infections that may cause disease in these circumstances include simian virus 40, cytomegaloviruses, and lymphocryptoviruses.

Finally, it should be recognized that outbred populations of nonhuman primates differ substantially from inbred rodent lines. Nonhuman primate populations have evolved with a spectrum of infectious agents for millions of years, and host adaptations have likely occurred to minimize the effects of these agents. Removal of ubiquitous, largely nonpathogenic infections from these populations may have unintended consequences.

Enveloped DNA Viruses

Poxviridae

Poxviruses are large (220–450 × 140–260 nm), brick- to ovoid-shaped enveloped viruses that replicate exclusively in the cytoplasm of infected cells. Their envelope is composed of lipid and tubular or globular protein structures that surround one or two lateral bodies and a dumbbell-shaped core containing a single molecule of double-stranded DNA. Virions have large genomes encoding approximately 200 polypeptides, at least one of which has homology with epidermal growth factor. This latter peptide acts to stimulate mitosis in neighboring cells and likely accounts for the proliferative epidermal and/or dermal lesions that characterize most poxvirus infections. The ability to induce cellular actin polymerization enhances cell-to-cell spread of virus. Poxviruses demonstrate independence from host cell transcriptional machinery due to the presence of virally encoded enzymes that are involved in transcription and modification of nucleic acids and proteins.

Five members of the poxvirus family belonging to Orthopoxvirus, Yatapoxvirus, and Molluscipoxvirus genera have been associated with naturally occurring epizootics in nonhuman primates (Table 1.1). Variola and vaccina infections of nonhuman primates represent significant experimental models.

TABLE 1.1. Poxviridae

Monkeypox

Introduction

The first reported outbreaks of monkeypox in nonhuman primates occurred in June 1958 at the Statens Seruminstitut in Copenhagen, Denmark, and shortly thereafter at the Biological Development and Control Laboratories of Merck Sharp and Dohme in West Point, Pennsylvania (von Magnus et al., 1959; Prier et al., 1960; Sauer et al., 1960). At that time, both institutes were importing large numbers of macaque monkeys for use in polio vaccine production. In both outbreaks, cynomolgus monkeys (Macaca fascicularis) were primarily affected, but at Merck a small number of rhesus monkeys (Macaca mulatta) also exhibited signs of the disease. Since then, there have been several additional outbreaks of monkeypox infection involving both New and Old World monkeys (Arita and Henderson, 1968; Arita and Henderson, 1976).

Etiology

Monkeypox virus is a member of the family Poxviridae, subfamily Chordopoxvirinae, and genus Orthopoxvirus. This genus includes variola (smallpox virus), vaccinia (smallpox vaccine virus), cowpox virus, and several other mammalian poxviruses. Immunologically, there is a close antigenic relationship among monkeypox virus, variola, and vaccinia. Monkeypox isolates are classified in two clades with distinct differences in virulence: the West African clade and the Congo Basin clade originating in Central Africa (Esposito and Knight, 1985; Likos et al., 2005).

Epizootiology

Unlike many other poxviruses, monkeypox virus has a wide range of permissive host species. This virus exists naturally in the tropical rain forests of western and central Africa (Brennan et al., 1980; Mutombo et al., 1983), where it causes subclinical endemic infections in several nonhuman primate species and a serious, sometimes fatal, smallpox-like disease in young people in these regions.

Ironically, despite the fact that the original outbreaks of monkeypox were in macaques imported from Malaysia, a subsequent serologic survey of 481 Malaysian monkeys failed to reveal a single animal seropositive to monkeypox virus (Arita et al., 1972). While rodents, particularly African squirrels, are thought to serve as the major viral reservoir, African green monkeys (Chlorocebus aethiops) have a high prevalence of antibodies to monkeypox virus with no evidence of clinical disease (Gispen et al., 1976; Khodakevich et al., 1987). It is likely that the macaques involved in the original outbreaks may have been incidentally exposed to infected African green monkeys during shipment from Asia. Monkeypox virus has a relatively broad natural host range that includes humans, anthropoid apes, and Old and New World monkeys. Primates in which monkeypox infections have been shown to occur include cotton-top tamarins (Saguinus oedipus), squirrel monkeys (Saimiri sciureus), African green monkeys, owl-faced monkeys (Cercopithecus hamlyni), rhesus monkeys, cynomolgus monkeys, hanuman langurs (Semnopithecus entellus), white-handed gibbons (Hylobates lar), orangutans (Pongo pygmaeus), gorillas (Gorilla gorilla), chimpanzees (Pan troglodytes), and human beings (Homo sapiens) (von Magnus et al., 1959; Peters, 1966; McConnell et al., 1968; Marennikova et al., 1976). In addition, a variety of rodent species, anteaters, pangolins, and birds from endemic areas of Africa have been shown to have antibodies to the virus.

Pathogenesis and Pathology

In the reported epizootics of monkeypox, transmission was thought to have occurred via aerosols, although the disease may more commonly be spread by direct contact and by biting insects (Mutombo et al., 1983). Viremia develops 3–4 days following experimental infection, at which time the virus disseminates to multiple sites, including skin, lung, mucous membranes, spleen, and gastrointestinal tract (Zaucha et al., 2001). Lesions within the skin initially appear as papules consisting of proliferative acanthocytes and progress to vesicles. Intracytoplasmic eosinophilic inclusions are apparent within acanthocytes. Vesiculation is followed by umbilication to form the classic pock lesion. Progressive dermal changes take place over a 4- to 14-day period. Lesions within the lung are similar, consisting of irregular foci of hemorrhagic necrosis. These may be responsible for more serious clinical sequelae and transmission of the virus by the aerosolized route. Paralleling epidemiologic observations in humans, experimental infections in cynomolgus macaques have demonstrated that isolates from the Congo Basin clade are associated with increased lesion severity, elevated levels of virus, and greater mortality relative to isolates from the West African clade (Chen et al., 2005; Saijo et al., 2009).

Clinical Findings

Clinical manifestations of monkeypox vary with the species affected. In general, a vesicular exanthema appears 6–7 days following experimental inoculation. Lesions are more often seen on the hands, feet, and face. The skin rash may be accompanied by constitutional signs and, in severe cases with respiratory tract involvement, the disease may be fatal.

Treatment

There is no specific treatment for monkeypox, but supportive therapy may prevent the death of animals with severe systemic disease. Most cases recover spontaneously after several weeks and animals are immune to subsequent infection by the same or related viruses.

Prevention

Vaccination against smallpox confers immunity to monkeypox infection in most cases (McConnell et al., 1968).

Zoonotic Potential

Human beings are susceptible to infection by monkeypox (Arita et al., 1985). The disease is seen sporadically in Africa and is usually not associated with direct nonhuman primate contact (Hutin et al., 2001; Meyer et al., 2002). The well-publicized 2003 outbreak in the Midwestern United States was the first documentation of human monkeypox in the western hemisphere (CDC, 2003; Reed et al., 2004b). Viral transmission in these cases was from contact with ill prairie dogs comingled with rodents imported from West Africa for the pet trade. In general, a febrile prodrome precedes development of lympadenopathy and characteristic pock lesions that disseminate over the entire body in a centrifugal pattern. Human-to-human transmission is inefficient with reintroduction of virus from animal reservoirs required to sustain infection (Fine et al., 1988; Hutin et al., 2001). Fatalities have been reported, and are more common in children.

Animal Models

Monkeypox has been used as a model organism in cynomolgus and rhesus macaques to support development of therapeutics and vaccines targeting variola (Hooper et al., 2004; Edghill-Smith et al., 2005b; Stittelaar et al., 2005, 2006; Earl et al., 2008; Marriott et al., 2008). Studies have included the use of SIV-inoculated macaques as a model of response to orthopoxvirus vaccination in the face of immunosuppression (Edghill-Smith et al., 2003, 2005a).

Variola

Variola is the prototypic Orthopoxvirus. Intensive vaccination programs resulted in eradication of the virus in the late 1970s although potential for use as a biological weapon has prompted continued research and classification of this virus, along with monkeypox, as a Department of Health and Human Services (HHS) select agent. To satisfy requirements for drug and vaccine licensure, nonhuman primate models of variola infection have been described. In a study by Jahrling et al., intravenous administration of high-dose virus to cynomolgus macaques resulted in an acutely lethal infection resembling hemorrhagic smallpox in man (Jahrling et al., 2004). Symptoms included fever, anorexia, cough, and viral exanthema followed by development of a severe hemorrhagic diathesis, multisystem organ failure, and death within 6 days of inoculation. Clinicopathologic findings included leukocytosis, thrombocytopenia, increased D-dimers, and elevated serum creatinine. Dermal lesions were characterized by erythema and hemorrhage with progression to typical vesiculopustlar lesions. Virus was disseminated systemically via a monocytic cell-associated viremia to lymphoid, gastrointestinal, hepatic, and renal tissues. Additional findings included significant cytokine elaboration and depletion of T-cell dependent regions of lymphoid tissue.

Vaccinia

Vaccinia is the live attenuated Orthopoxvirus used in the smallpox vaccine. Attenuated strains, such as modified vaccinia virus Ankara, have been widely used in nonhuman primate animal models as vectors for recombinant vaccines designed to prevent diseases such as human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), influenza, and viral encephalitides. While attenuated, ocular exposure in laboratory workers can lead to severe keratoconjunctivitis and vision loss and appropriate personal protective equipment should be worn. Following intradermal injection a localized proliferative dermatitis develops and the host remains infectious until the crust is lost in 14–28 days (Figure 1.1).

FIGURE 1.1 Poxviridae infections. Intradermal inoculation of vaccinia virus produces a typical pox lesion in the skin (A) which heals within 21 days (B). Histologically eosinophilic intracytoplasmic inclusions are typical of pox virus infections (C). Ultrastructurally viral particles have a dumbbell appearance by electron microscopy (D).

Cowpox

Cowpox is an Orthopoxvirus reported in both New and Old World primates (Martina et al., 2006; Matz-Rensing et al., 2006). The first report in common marmosets (Callithrix jacchus) may actually be a 1982 epizootic originally attributed to a Yatapoxvirus. Clinical disease was characterized by the appearance of erythematous papules progressing through vesiculation and umbilication over a 4- to 6-week course (Gough et al., 1982). Lesions were concentrated on the face, scrotum, and palmar or plantar surfaces. Identification of the etiologic agent was based on ultrastructural examination. A more recent report describes development of hemorrhagic dermal lesions with an identical distribution in a colony of marmosets and Saguinus species (Matz-Rensing et al., 2006). Viral etiology was determined using molecular techniques to be a poxvirus with close homology to cowpox. Skin lesions from both reports were characterized by acanthosis with epidermal necrosis, ulceration, and typical pox-like intracytoplasmic inclusions. Disease may be fatal in New World monkeys. Transmission occurs via contact with rodent vectors which have a geographic distribution over much of Europe, Asia, and Africa but are not present in North America. Cowpox is considered a zoonotic disease resulting in localized, self-limiting infection in immunocompetent individuals.

Yaba Monkey Tumor Virus

Introduction

In 1957 an outbreak of subcutaneous tumors was observed in a group of captive macaques housed in Yaba, Nigeria (Bearcroft and Jamieson, 1958). A viral etiology was subsequently demonstrated and confirmed as a poxvirus. Yaba monkey tumor virus (YMTV) has been shown to naturally infect macaques (M. mulatta, M. fascicularis, and M. arctoides) and baboons (Papio anubis) (Downie, 1972). Experimentally, the pig-tailed macaque (M. nemestrina), stump-tailed macaque (M. arctoides), African green monkey, sooty mangabey (Cerocebus atys), and the Patas monkey (Erythrocebus patas) are susceptible (Kupper et al., 1970). Accidental and experimental human infection have been demonstrated. New World primates are resistant.

Etiology

YMTV is included in the genus Yatapoxvirus with tanapoxvirus and Yaba-like disease virus.

Epizootiology

Relatively few naturally occurring episodes have been documented. Captive-born African monkeys appear susceptible to experimental infection, whereas wild-caught animals are resistant, suggesting that widespread infection with YMTV or closely related virus(es) occurs in the wild, conferring life-long immunity to those individuals at an early age. The method of transmission is unknown, but arthropod vectors, tattoo needles, and trauma have been suggested as possible mechanisms.

Clinical Findings

The original outbreak of YMTV disease in rhesus macaques was characterized by multiple subcutaneous masses, often on the hands and feet, varying in size from small papules to nodules several centimeters in diameter. Larger masses would occasionally ulcerate and all masses invariably regressed by 6 weeks. Animals often developed new lesions as old lesions regressed. Subsequent cases and outbreaks have had a similar clinical course (Bruestle et al., 1981; Walker et al., 1985; Whittaker and Glaister, 1985; Schielke et al., 2002). Oral masses have been described in baboons (Bruestle et al., 1981). Intravenous inoculation may produce lesions in many organs, including lung, muscle, heart, and pleura. Because masses spontaneously regress, they are often called pseudotumors. Aerosol transmission of YMTV has been demonstrated experimentally in rhesus and cynomolgus macaques (Wolfe et al., 1968). Inoculated animals developed nasal, pulmonary, and pleural tumors but did not transmit the virus horizontally to cagemates.

Pathogenesis and Pathology

The characteristic histopathologic lesion consists of large pleomorphic histiocytic cells forming a nonencapsulated and infiltrative mass. These cells have hyperchromatic nuclei and prominent nucleoli. Mitotic figures are frequent. Large eosinophilic intracytoplasmic inclusion bodies may be evident. Regression is associated with erosion, ulceration, and formation of multinucleated cells.

Zoonotic Potential

Both experimentally induced and spontaneous diseases have been recognized in humans. In spontaneous human cases, lesions were most often noted on hands and feet and were associated with lymphadenopathy and fever. As in nonhuman primates, regression occurred within weeks.

Yaba-Like Disease Virus

Introduction

In 1967 an outbreak of a contagious skin disease of macaques and human handlers was observed at three primate facilities in Oregon, Texas, and California (Or-Te-Ca) and was traced to a single primate importer (Hall and McNulty, 1967; Crandell et al., 1969; Downie et al., 1971). Affected species in the original outbreak were rhesus macaques, pig-tailed macaques, Japanese macaques (M. fuscata), and Sulawesi-black macaques (Macaca nigra).

Etiology

Yaba-like disease virus (YLDV) is classified in the genus Yatapoxvirus. This virus was initially thought to be tanapox, a relatively benign cutaneous infection of humans responsible for periodic outbreaks of illness in East Africa (Jezek et al., 1985). It has been documented that these viruses have 98.6% identity of genomic sequences. Current understanding is that these are two different strains of the same virus with tanapox representing the human virus and YLDV representing the nonhuman primate virus (Brunetti et al., 2003). Or-te-ca poxvirus and benign epidermal monkeypox (BEMP) are also names used historically to denote this virus.

Epizootiology

The unique circumstances responsible for the initial outbreak of YLDV infection in macaques are unrecognized. Serologic surveys indicate natural infection of African but not New World primates (Downie, 1972; Downie and Espana, 1974).

Pathogenesis and Pathology

Histologically, papules are composed of focally extensive regions of epidermal proliferation and ballooning degeneration and arise after a 4- to 6-day incubation period (Casey et al., 1967; Downie and Espana, 1972). Hair follicles and sebaceous glands may be involved. Eosinophilic, intracytoplasmic viral inclusions may be present. Nuclei are variably distended by large eosinophilic cytoplasmic invaginations. Ultrastructurally mature viral particles are 370 × 150 μm in size and have an outer coat consisting of seven distinct layers and an inner dumbbell-shaped core. Morphologically, these are indistinguishable from YMTV (Casey et al., 1967). Resolution is characterized by necrosis, ulceration, and infiltration of the dermis by a variety of inflammatory cells.

Clinical Findings

Following a 4- to 5-day incubation period, small red papules form and progress by 14 days to circular, firm raised foci up to 1 cm in diameter. These lesions may ulcerate and become umbilicated before resolving in 3–4 weeks and are often surrounded by a hyperemic border.

Treatment

No treatment is available.

Prevention

Previous infection with YLDV is protective against subsequent challenge. Vaccination with vaccinia does not produce protective immunity.

Zoonotic Potential

The related human virus, tanapox, occurs naturally in regions of Kenya and Congo. The initial outbreaks in 1957 were associated with flooding of the Congo River. The definitive host and vector(s) involved in these epidemics are unknown. Transmission of YLDV from infected monkeys to humans has been documented. In humans, infection is characterized by a short febrile illness accompanied by constitutional signs. As these signs abate, small nodules and papules arise eventually, forming the classic pock lesion.

Molluscum Contagiosum

Molluscum contagiosum is a chronic, mildly contagious skin disease of humans characterized by multiple small, pinkish skin nodules from which a waxy material may be extruded. Although it is caused by a pox virus, it is difficult to culture in vitro, and attempts at experimental infection of a variety of nonhuman primates have been unsuccessful. Histologically, the lesion is composed of a flask-shaped proliferative nodule of epidermal cells in which centrally enlarged acanthocytes contain homogeneous, intracytoplasmic, eosinophilic viral inclusions. These molluscum bodies are shed along with keratin debris through a central pore. A single outbreak with similar clinical and histopathologic findings has been described in chimpanzees (Douglas et al., 1967). It is unknown whether this represented a similar or identical viral agent to that seen in the human disease.

Herpesviridae

The family Herpesviridae is divided into three distinct subfamilies: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae (Table 1.2). Specific viruses will be discussed herein according to their subfamily grouping. Additionally, there are a number of herpesviruses that have yet to be assigned to a subfamily. The classification of herpesviruses has been recently updated by the International Committee of the Taxonomy of Viruses (ICTV) resulting in a number of name changes (Davison et al., 2009). Names for the nonhuman primate herpesvirus species are based on the host genus with the name ending in –ine (i.e. Macacine herpesvirus 1 replaces Cercopithicine herpesvirus 1). Current taxonomic designations with the former and common names are presented in Table 1.2. Although the viral subfamilies are distinctly different, as a group the herpesviruses do share certain genetic and biologic properties. These include (1) a complex double-stranded DNA genome encoding a number of enzymes involved in protein processing, DNA synthesis, and nucleic acid metabolism; (2) DNA synthesis and capsid formation in the nucleus; (3) requisite destruction of the host cell to complete the viral replicative process; and (4) viral persistence in a latent form within the host.

TABLE 1.2. Herpesviridae

∗ Tentative species within the genus.

Alphaherpesvirinae

Macacine Herpesvirus 1: Herpes B Virus

Introduction

Herpes B virus occurs as a common, latent, and usually asymptomatic infection of Asian macaques and has been demonstrated by viral isolation or serology to occur in rhesus macaques, bonnet macaques (M. radiata), Japanese macaques, stump-tailed macaques, Formosan rock macaques (M. cyclopis), pig-tailed macaques, lion-tailed (M. silenus), and cynomolgus macaques (Hunt and Blake, 1993a; Anderson et al., 1994; Thompson et al., 2000). Although rarely responsible for disease in the natural host, inadvertent infection of humans results in a disseminated viral infection characterized by ascending paralysis and a high case fatality rate. The increased incidence of human cases in the late 1980s and early 1990s combined with the 1997 death of a primate center research assistant has spurred continued interest in the prevention and treatment of this disease. Infection of non-macaque species, including the Patas monkey, black and white colobus (Colobus abyssinicus), DeBrazza’s monkey (Cercopithecus neglectus), capuchin monkey (Cebus apella), and common marmoset, has reportedly produced fatal disease (Gay and Holden, 1933; Loomis et al., 1981; Wilson et al., 1990; Thompson et al., 2000). Persistent and asymptomatic B virus infection in a colony of capuchin monkeys housed near but not in direct contact with rhesus macaques has been reported and indicates that safe practices should be employed when working with all nonhuman primate species (Coulibaly et al., 2004).

Etiology

Herpes B virus is a member of the subfamily Alphaherpesvirinae and genus Simplexvirus. The 157-kb-long viral genome encodes approximately 70 proteins. Homologs of all of these genes occur in related viruses of humans, such as Human herpesvirus 1 and 2 (HHV1 and HHV2; Herpes simplex virus 1 and 2), and of primates, such as Papiine herpesvirus 2 (Herpesvirus papio 2) and Cercopithecine herpesvirus 2 (Ohsawa et al., 2002a, 2003; Perelygina et al., 2003b). Notably, herpes B virus lacks a homolog of the HHV neurovirulence gene γ134.5 suggesting alternate strategies to promote replication of B virus within neurons (Perelygina et al., 2003b). The viral envelope contains at least nine glycoproteins that are targets of the immune response and help to define cellular tropism. Glycoproteins B and D have 80% and 56% identity with the respective HHV1 glycoproteins, while glycoproteins G and C demonstrate significant sequence variation (Ohsawa et al., 2002a; Perelygina et al., 2002). Genomic sequencing and restriction fragment length polymorphism analysis have demonstrated that distinct genotypes of herpes B virus occur in different species of macaques including rhesus, cynomolgus, pig-tailed, lion-tailed, and Japanese macaques (Smith et al., 1998; Thompson et al., 2000; Ohsawa et al., 2002b). The parallel arrangement of phylogenic trees for B virus isolates and mitochondrial DNA sequences from the respective macaque species indicates probable co-speciation. Viral replication occurs rapidly, with enveloped capsids present 8–10 h after infection. In cell culture, syncytial cells and Cowdry-type A intranuclear inclusions are readily apparent.

Epizootiology

The incidence of infection in immature rhesus macaques is low and increases rapidly with sexual maturity, approaching 80–90% in some colonies by 3–4 years of age (Weigler et al., 1993; Andrade et al., 2003; Sariol et al., 2006). The percentage of animals with active oral lesions is much less and in one large study of 14 400 macaques was found to be 2.3% (Keeble, 1960). The virus is transmitted through sexual or biting behavior and by fomites. In overcrowded or unsanitary conditions, animals may become infected at an earlier age and the seropositive rate may be higher. Animals remain infected for life and may periodically shed the virus in oral and genital secretions. The greatest risk of primary infection occurs during the breeding season in sexually adolescent animals 2–3 years of age (Weigler et al., 1990, 1993).

Pathogenesis and Pathology

The pathogenesis of herpes B infection in macaques is similar to HHV1 infection in humans. Primary infection results in an initial round of replication at the site of inoculation. Histologically, this is characterized by the ballooning degeneration of keratinocytes with progression to vesiculation. Multinucleated, syncytial cells and eosinophilic to basophilic, intranuclear viral inclusions may be prominent. Immunohistochemistry utilizing antibodies against HHV1 can be used to demonstrate viral antigen in equivocal lesions. Inflammatory cells may be found within vesicles, epidermis, and subjacent dermis. Endothelial cell necrosis with intranuclear viral inclusions may be seen. In disseminated disease, there is widespread, hemorrhagic necrosis within the liver, lung, brain, adrenal gland, and lymphoid organs (Espana, 1973; Simon et al., 1993; Anderson et al., 1994; Carlson et al., 1997). Herpes B virus should be included in the list of viral agents responsible for multifocal, necrotizing hepatitis in macaques.

Seroconversion occurs soon after primary infection and is associated with the resolution of clinical signs. These antibodies may be detected by enzyme-linked immunosorbent assay (ELISA) and western blot methods (Ward and Hilliard, 1994, 2002). False-negative tests and latently infected immunologically unreactive individuals complicate the interpretation of results on single samples. Various strategies have been explored to increase the sensitivity and specificity of serodiagnosis and improve biosafety including assays based on recombinant glycoproteins and surrogate antigens such as HHV1, Papiine herpesvirus 2, and Cercopithicine herpesvirus 2 (Ohsawa et al., 1999; Takano et al., 2001; Yamamoto et al., 2005). The variable antigenic cross-reactivity of certain glycoprotein epitopes may also allow for discrimination of antibodies to closely related alphaherpesviruses (Perelygina et al., 2002; Perelygina et al., 2005; Fujima et al., 2008). A number of strategies for virus speciation via polymerase chain reaction technology have also been described (Hirano et al., 2002; Perelygina et al., 2003a; Oya et al., 2004; Miranda et al., 2005). PCR detection has decreased sensitivity and utility due to the infrequency of virus shedding.

Following initial viral replication, the virus (virion or capsid) is transported by retrograde axonal flow to the sensory ganglion where a latent infection is established for the life of the animal. Centrifugal spread may contribute to the enlargement of lesions or generalization during primary infection. Factors contributing to recrudescence are poorly understood, but stress, fever, ultraviolet light, tissue or nerve damage, and immunosuppression have been identified clinically as contributing factors in the reactivation of HHV in humans and may play a similar role with B virus in macaques. It is generally thought that stress related to changing social dynamics, transportation, or relocation can result in reactivation of herpes B virus (Mitsunaga et al., 2007; Elmore and Eberle, 2008). Detection of shedding, although uncommon, appears to be most strongly associated with the breeding season (Weigler et al., 1993; Huff et al., 2003). Other studies have shown that viral shedding in seropositive macaques was not commonly associated with common laboratory procedures or occurrences such as quarantine, parturition, and chair restraint (Weir et al., 1993; Huff et al., 2003). Reactivation of oral lesions has been described in macaques treated with immunosuppressive agents and with solid organ transplantation drug regimens (Chellman et al., 1992). Interestingly, reactivation is not commonly recognized in macaques experimentally inoculated with SIV and dying with acquired immunodeficiency syndrome (AIDS) (Simon et al., 1993) (Figure 1.2).

FIGURE 1.2 Macacine herpesvirus 1 (B virus (BV)). BV infection of mucosal surfaces may be observed with primary infection or reactivation and often appear first as small vesicles (A). In severe cases these may spread to adjacent haired skin (B) and disseminate to the gastrointestinal tract (esophagus, C). The virus may be sexually transmitted and lesions appear on the penile (D) and vaginal mucosa. (Photographs courtesy of Drs. Dan Anderson and Sherry Klumpp, Yerkes National Primate Research Center, with permission.)