JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

April 2023

N-V14

 

Signalment (JPC #2131424): 1-year-old male Rhesus monkey (Macaca mulatta)  

 

HISTORY: This macaque was inoculated with simian immunodeficiency virus (SIV). He developed persistent diarrhea, progressive weight loss, and died 130 days later.

  

HISTOPATHOLOGIC DESCRIPTION: Cerebrum: Multifocally and randomly disrupting and replacing gray and white matter architecture are occasional scattered nodules measuring up to 250 µm in diameter composed of macrophages with abundant foamy, eosinophilic cytoplasm, few multinucleated giant cells with up to 5 nuclei, and eosinophilic and karyorrhectic debris (necrosis). Virchow-Robin space is mildly expanded by either similar inflammatory cells or increased clear space (edema). Multifocally, throughout the white matter, there is mild spongiosis characterized by variably sized vacuoles measuring up to 20 µm.

 

MORPHOLOGIC DIAGNOSIS: Cerebrum: Encephalitis, granulomatous, multifocal and peri­vascular, mild, Rhesus monkey (Macaca mulatta), nonhuman primate.

 

ETIOLOGICAL DIAGNOSIS: Lentiviral encephalitis

 

CAUSE: Simian immunodeficiency virus (SIV)

 

CONDITION: Simian immunodeficiency virus encephalitis (SIVE)

 

CONDITION SYNONYMS: Giant cell encephalitis

 

GENERAL DISCUSSION:

• Enveloped single-stranded RNA virus in the family Retroviridae, subfamily Lentiviridae
• Closely related to human immunodeficiency virus (HIV); extensive investigation as animal model for HIV infection
• Like other retroviruses, SIV contains 3 major structural genes:
  1. env: Transmembrane and envelope proteins
  2. pol: Reverse transcriptase (RT) and integrase enzymes; RT transcribes RNA into dsDNA; integrase enables DNA provirus to integrate into host genome
  3. gag: Structural capsid proteins; encodes glycoprotein gp120 and gp41; mediate fusion of viral envelope with host cell plasma membrane 
• Serotype identification is based on species infected (e.g., SIVmac = Macaca

             mulatta); >40 SIV isolates recognized in African species

• There are several species of Old-World wild nonhuman primates that harbor host adapted serotypes, including guenons, baboons, mangabys, African green monkeys (including vervets), chimpanzees, and western lowland gorillas; up to 60% prevalence in wild African populations
• Natural hosts develop a persistent viral infection and are typically asymptomatic but can rarely develop simian acquired immunodeficiency syndrome (SAIDS); introduction into an aberrant host (rhesus macaques) will cause an AIDS-like disease
• SIV in wild rhesus macaques has not been identified; however, Asian macaques are highly susceptible and SIV can rapidly spread in a colony via horizontal transmission; the disease is prevalent in captive animal colonies where it causes an AIDS-like disease
• Prodromal period can be months to years before the onset of clinical signs 
• Zoonotic; natural disease not reported in New-World nonhuman primates   

 

PATHOGENESIS:

• Transmission in natural hosts occurs both horizontally and vertically; sexual intercourse and fighting are likely significant modes of transmission
• Viral tropism for CD4+ cells (monocytes/macrophages, CD4+ lymphocytes, and antigen presenting dendritic cells) > cellular entry mediated by interactions between gp120 (anchored by gp41), CD4 molecule, and CCR5 coreceptor > viral ssRNA transcribed into DNA via RT and integrated into host cell DNA via integrase > transcription of proviral DNA > progeny virions bud from cell membrane (predominantly lymphocytes) 
• Infection results in profound decline in CD4+ lymphocytes in macaques > immunosuppression > lymph node and splenic depletion > lymphopenia > predisposition for opportunistic infection and lymphoma (B-cell most common)
• Encephalopathy is multifactorial; unclear if lesions are related to viral burden within the CNS or the secretion of cytokines and other damaging substances by relatively few infected cells 
• SIV infects mainly microglial cells or macrophages and results in:
  • Cytokines such as tumor necrosis factor (TNF) and interleukins (eg IL-1, IL-6)
  • Other potentially damaging chemicals such as nitric oxide, superoxide anion, hydroxyl radicals, peroxides, and quinolates
• Simian lentiviral infection induces the following:
  • Elevated endothelial vascular cell adhesion molecule-1 (VCAM-1)
  • Elevated endothelial and/or perivascular macrophage expression of chemokines (MIP-1alpha, MIP-1beta, RANTES)  
  • Over-expression of chemokine receptors (CCR3, CCR5, CXCR3, CXCR4) on virus infected macrophages, multinucleated giant cells, and lymphocytes
  • Result:  
    • Increased numbers of infected monocytes/macrophages migrating across the blood-brain barrier > release of neurotoxic cytokines > neuronal injury and death
    • Chemokine receptor on neurons (CCR5) allows direct interaction with virus   > virus alters cell signaling > abnormal neuronal cellular function 

 

TYPICAL CLINICAL FINDINGS:

• Initial (weeks): Disseminated cutaneous eruption (rash) affecting groin, medial thighs, trunk, and face, generalized lymphadenopathy, diarrhea, pneumonia 
• Later: Wasting syndrome and chronic enteritis are the most common clinical sign in affected macaques; opportunistic infections (viral, bacterial, protozoal, metazoal, and fungal) secondary to lymphoid depletion
• Severity of neurologic signs depends on host species, viral strain, and viral RNA concentrations in various brain regions; there may or may not be cognitive impairment

 

TYPICAL GROSS FINDINGS:  

• Nervous
  • Increased amount of subdural blood-tinged CSF
  • Congested brain surface
  • Decreased thickness of cortical gyri and sulci (atrophy)
• Lesions independent of immunosuppression in other organs
  • Skin: Disseminated cutaneous eruptions (rash)
  • Gastrointestinal tract: Enteritis; +/- fulminant necrohemorrhagic gastroenteritis
  • Cardiopulmonary: Interstitial pneumonia, +/- proliferative arteriopathy, right atrial and pulmonary thrombosis, and infarction
  • Nervous: Listed above
  • Lymphoid: Varies from lymphoid hyperplasia (early) to follicular involution (late)

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Lesions independent of immunosuppression (direct viral actions)
  • Skin: Non-descript superficial and perivascular lymphocytic dermatitis with variable swelling and degeneration of the epidermis
  • Gastrointestinal tract: Villous blunting and atrophy, crypt hyperplasia, CD4 T-cell loss
  • Respiratory:  
    • Interstitial pneumonia with syncytial cells
    • Extensive medial and intimal proliferation of medium and large sized pulmonary arteries, and often associated with thrombosis and infarction of pulmonary       parenchyma
  • Nervous: 
    • Granulomatous encephalitis: Macrophages, multinucleated giant cells, microglial nodules; affects both grey and white matter of brain and spinal cord
    • Perivascular cuffing by macrophages, multinucleated giant cells, and fewer lymphocytes, especially in the white matter; astrogliosis; white matter spongiosis and demyelination; neuronal degeneration and loss
  • Lymphoid:  Six patterns that are not mutually exclusive and may coexist (1)     normal morphology, (2) follicular hyperplasia, (3) follicular involution with normal or expanded paracortical regions, (4) depletion of follicular and paracortical regions, (5) granulomatous (giant cell) lymphadenitis, (6) generalized lymphoproliferative syndrome 
• Active opportunistic infections (typically <300-400 CD4+ T cells/mm³):   Cytomegalovirus, adenovirus, polyomavirus (SV40), Pneumocystis carinii, Mycobacterium avium complex, Cryptosporidium spp., Cryptococcus neoformans, Toxoplasma gondii, Trichomonas spp., Plasmodium spp., and Candida albicans (described elsewhere)

 

ULTRASTRUCTURAL FINDINGS:

• Lentiviral particles: Membrane bound cytoplasmic vacuoles in macrophages and syncytial cells
• Multinucleated giant cells may have myelin inclusions

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Immunohistochemistry:  
  • CD68 – expressed by large multinucleated syncytial cells indicating macrophage/monocyte lineage

 

DIFFERENTIAL DIAGNOSIS:

Other retroviruses in macaques:  

• Macaques are natural hosts for 3 exogenous retroviruses that may cause immunosuppression or lymphoproliferative disease: 
  • Simian type D retrovirus: The most important cause of immunosuppression in macaques, and results in broad spectrum of disease from subclinical to rapidly fatal immunosuppressive disease
  • Simian T lymphotropic virus (retrovirus, oncornavirus subgroup): Vast majority of infections are clinically silent, and only a small proportion of infected animals develop T-cell lymphoma or lymphoproliferative disease
  • Simian foamy virus (SFV, retrovirus, spumavirus subgroup):  Mostly non-pathogenic, infects wide variety of tissues and potential candidate for a viral vector for gene therapy

Other causes of encephalitis in non-human primates:

• Protozoal:
  • Toxoplasma gondii:   Cysts smaller than E. cuniculi with crescent shaped tachyzoites
  • Balamuthia mandrillaris (amoeba):  Acute suppurative meningoencephalitis, microgranulomas, vasculitits, gram positive organisms
  • Acanthamoeba sp., Naegleria sp.:  Multifocal to coalescing necrotizing neutrophilic meningoencephaltis and pneumonitis with trophozoites and cysts
  • Encephalitozoon cuniculi:   Granulomatous encephalitis or meningoencephalitis; Gram positive oval rods that are also Giemsa positive
  • Trypanosoma cruzi:   Similar to T. gondii but contain a kinetoplast
• Viral:
  • Acute measles encephalitis (morbillivirus):   Progressive gliosis, demyelination, and neuronal loss with intranuclear inclusions and a nonsuppurative, perivascular meningoencephalitis
  • Cytomegalovirus (betaherpesvirus):   Involves primarily the leptomeninges and subjacent neuropil with perivascular cuffing, neutrophilic infiltrates, necrosis, fibrinous exudate, edema and large basophilic intranuclear inclusion bodies and/or granular eosinophilic cytoplasmic inclusion bodies
  • SV40 (Polyomavirus, U-V09):  Two separate manifestations.
    • Progressive multifocal leukoencephalopathy with demyelination; bizarre shaped astrocytes and oligodendroglia with enlarged nuclei and intranuclear inclusion bodies; occurs due to virus reactivation)
    • Meningoencephalitis without demyelination; virus in astrocytes instead of oligodendrocytes; occurs due to primary infection with SV40
  • Human herpes simplex virus: Necrotizing encephalomyelitis, intranuclear inclusion bodies, syncytial cells (similar to what Macacine herpesvirus 1 [B virus] causes in humans)
• Bacterial:
  • Streptococcus pneumoniae (N-B08):  The most common cause of fibrinopurulent meningitis/meningoencephalitis in nonhuman primates; causes severe fibrinopurulent leptomeningitis, markedly congested meningeal vasculature, and necrotizing vasculitis with thrombosis in the meninges, gray matter, and white matter 
  • Mycobacterium tuberculosis and M. bovis:  Multifocal cerebral granulomas with rare acid fast positive bacilli (paucibacillary)
  • Klebsiella pneumoniae:   Meningitis, gram negative bacteria with prominent capsules
  • Listeria monocytogenes:   Purulent meningoencephalitis, gram positive rods
• Fungal:
  • Cryptococcus neoformans:   Meningoencephalitis, narrow based single budding, and granulomatous changes

 

COMPARATIVE PATHOLOGY:

• Other immunodeficiency viruses:  Human (HIV), feline (FIV), and bovine (BIV)
• Other lentiviruses:  Equine infectious anemia (EIA), small ruminant lentivirus (N-V13, formerly caprine arthritis and encephalitis virus (CAEV) and Visna-Maedi virus)

 

References:  

1. Fahey MA, Westmorland SV. Nervous system disorders of nonhuman primates and research models. In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases. Vol 2. 2^nd ed. San Diego, CA: Academic Press; 2012:759-762. 
2. Lowenstine LJ, McManamon R, Terio KA. Apes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:391-2. 
3. Lowenstine LJ, Osborn KG. Respiratory system diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases. Vol 2. 2^nd ed. San Diego, CA: Academic Press; 2012:418, 441, 448-9.
4. Matz-Rensing K, Lowenstine LJ. New World and Old World Monkeys. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:354. 
5. Wachtman L, Mansfield K. Viral diseases in nonhuman primates. In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases. Vol 2. 2^nd ed. San Diego, CA: Academic Press; 2012:56-7, 62-70.

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