JPC SYSTEMIC PATHOLOGY
Signalment (AFIP #2329759): 2-year-old male rhesus monkey
HISTORY: This 2-year-old male rhesus monkey was born at the primate center and entered in a study of simian immunodeficiency virus pathogenesis. He was inoculated with SIVmac251 and died 1 year later.
HISTOPATHOLOGIC DESCRIPTION: Kidney: Diffusely and moderately expanding the cortical interstitium, loosely arranged fibrous connective tissue, scattered individual and rare aggregates of lymphocytes and plasma cells surround and separate tubules, which are often atrophic in areas of fibrosis. Tubules are multifocally ectatic and/or contain pale eosinophilic granular material (protein) or few sloughed epithelial cells. Tubules are often lined by enlarged epithelial cells that appear multiple layers deep (hypertrophy and hyperplasia). Multifocally, tubular epithelium is attenuated (flattened), degenerate (swelling and cytoplasmic vacuolization), necrotic (shrunken with karyolytic and pyknotic nuclei), or regenerative (basophilic cells with large vesiculate nuclei). Multifocally low numbers of 6-8 um, round to angular, basophilic intranuclear viral inclusion bodies are present within tubular epithelial cells and the parietal epithelial cells of Bowman’s capsule. Focally, glomeruli have hypertrophic parietal and visceral epithelial cells and occasionally exhibit synechia (adherence to Bowman’s capsule).
MORPHOLOGIC DIAGNOSIS: Kidney: Nephritis, tubulointerstitial, lymphocytic, chronic, diffuse, moderate, with tubular degeneration, necrosis, and regeneration, moderate interstitial fibrosis, and epithelial intranuclear viral inclusion bodies, Rhesus monkey (Macaca mulatta), primate.
ETIOLOGIC DIAGNOSIS: Polyomaviral nephritis
CAUSE: Simian virus 40
- Vacuolating agent infection
- Simian papovavirus infection
- Simian polyomavirus
- Progressive multifocal leukoencephalopathy
- Polyomaviral interstitial pneumonia
- Papovaviral tubulointerstitial nephritis
- Usually an inapparent infection in natural hosts (Asian macaques, especially rhesus, cynomolgus; old world primates); high incidence of infection
- Overt disease only in immunocompromised individuals, such as those co-infected with SIV
- Lesions in brain, kidney and lung and other tissues
- This is a DNA virus in the Polyomavirus genus of the family Polyomaviridae
- Oncogenic in non-host species (e.g., hamster, people)
- Disease symptoms result from reactivation of latent infection that originally occurred early in life (in kidney, CNS and circulating lymphocytes) or primary infection later in life during periods of immunosuppression
- In macaques, exposure to SV40 occurs early in life, most likely associated with mild respiratory illness; infection is associated with viremia, and shedding occurs in nasopharyngeal secretions, urine and feces; many adults are serologically positive; in the immunocompetent natural host, the virus remains latent, primarily in renal tissue
- CNS disease includes progressive multifocal leukoencephalopathy, and a second CNS manifestation without demyelination has been described in SIV-inoculated macaques; infection of astrocytes rather than oligodendrocytes predominates causing a meningoencephalitis
- It is postulated that the nephritis, pneumonia, and meningoencephalitis occur if the animal is immunocompromised prior to developing SV40, and the progressive multifocal leukoencephalopathy occurs if the animal is infected with SV40 (early in life) first and then becomes immunosuppressed, which reactivates the latent SV40 infection
- Recent report of mesenchymoproliferative enteropathy in small intestine of rhesus macaque associated with SV40 (and cytomegalovirus co-infection)
TYPICAL CLINICAL FINDINGS:
- No overt disease in immunocompetent individuals
- In immunocompromised individuals, clinical signs will be related to interstitial nephritis, pneumonia, meningoencephalitis, or progressive multifocal leukoencephalopathy in addition to other diseases related to the immunosuppression disease
TYPICAL GROSS FINDINGS:
- Renal lesions have been postulated to predominate in macaques acquiring infection during immunosuppression; CNS lesions are more likely following recrudescence of latent infection
- Kidneys: Multiple linear petechiae in inner cortex and medulla
- Lung: Patchy firm, red areas that do not collapse and have a frothy fluid
- Brain: Multifocal to coalescing 1–3 mm gray-white, translucent foci in white matter of cerebrum and brainstem
- Clinical disease should prompt a search for an underlying immunosuppressive agent
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Kidney: collecting tubules lined by hypertrophic or hyperplastic epithelium in inner cortex and medulla; there are occasionally large deeply basophilic intranuclear viral inclusion bodies in tubular or parietal epithelial cells (prominent and visible at low magnification); may also be present in sloughed tubular epithelial cells; there is chronic nonsuppurative tubulointerstitial nephritis, fibrosis, and glomerulosclerosis
- Lung: Proliferative interstitial pneumonia, with intranuclear inclusions within hypertrophied type II pneumocytes
- Brain: Multifocal to coalescing areas of demyelination of subcortical white matter and in subependymal regions; large basophilic intranuclear inclusions within oligodendrocytes and astrocytes; giant reactive astrocytes; perivascular cuffing (progressive multifocal leukoencephalopathy); neurons may also be infected
- 45 nm virions that often form paracrystalline arrays and fill the nucleoplasm of cells
- Fewer virions in the cytoplasm
ADDITIONAL DIAGNOSTIC TESTS:
- Serology is of little value since most rhesus monkeys are seropositive
- EM and in situ hybridization are diagnostic
DIFFERENTIAL DIAGNOSIS: Viruses causing inclusion bodes can be differentiated based on size, using electron microscopy, or antigenic or genetic composition using virus-specific immunohistochemistry
- Adenovirus: Very large basophilic intranuclear inclusion bodies with a “smudgy” appearance that fill the nucleus within mesenchymal cells; uncommon cause of tubulointerstitial nephritis in nonhuman primates
- Cytomegalovirus: Large basophilic intranuclear inclusions with a clear halo (“owl eye”) within epithelial cells
- Herpesvirus simiae (B virus): eosinophilic inclusion bodies
- Other herpesviruses
- Hamsters: Oncogenic in suckling hamsters when experimentally infected; tumor type based on age and method of inoculation
- Humans: Contamination of rhesus kidney cell cultures by SV40 used in the early production of polio vaccines
- Other polyoma viruses
- Budgerigar fledgling disease: A highly contagious and fatal disease of young budgerigars and non-budgerigar psittacines with karyomegalic cells with prominent intranuclear inclusion bodies in many tissues
- Hamster polyoma virus: Causes transmissible lymphoma in hamsters; can occur in epizootics; trichoepitheliomas also possible.
- Raccons: Olfactory tumors (sarcomas) associated with polyomavirus
- Standardbred horses (N=2): tubular necrosis and tubulointerstitial nephritis associated with equine polyomavirus
- Cynomolgus polyoma virus (CPV): A virus of cynomolgus monkeys that is antigenically and genomically related to SV40 and causes tubulointerstitial nephritis in immunosuppressed monkeys
- K virus of mice: Experimental disease; oral inoculation of neonatal mice causing respiratory distress and death
- Polyoma viral infection of mice: Experimental infection of mice that causes tumors
- Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed Ames, IA: John Wiley & Sons, Inc; 2016:176-177.
- Cummins Macri S, Knight HL, Miller AD. Mesenchymoproliferative Enteropathy Associated With Dual Simian Polyomavirus and Rhesus Cytomegalovirus Infection in a Simian Immunodeficiency Virus–Infected Rhesus Macaque (Macaca mulatta). Vet Pathol. 2013; 50(4):715-721.
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- Giannitti F, Higgins RJ, Pesavento PA, et al.Temporal and geographic clustering of polyomavirus-associated olfactory tumors in 10 free-ranging raccoons (Procyon lotor). Vet Pathol. 2014 ;51(4):832-45.
- Jennings SH, Wise AG, Nickeleit V et al. Polyomavirus-associated nephritis in 2 horses. Vet Pathol. 2013; 50(5): 769-774.
- Wachtman L, Mansfield K. Viral diseases. In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases. Vol 2. 2nd ed. London, UK: Elsevier;2012:30-33.