JPC SYSTEMIC PATHOLOGY
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 normal architecture of the gray and white matter, there are scattered nodules up to 250 microns 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). Few neuronal cell bodies have centralized clearing with peripheralization of the Nissl substance (central chromatolysis). Virchow-Robin space is either mildly expanded by similar inflammatory cells or increased clear space (edema). Multifocally, throughout the white matter, there are many varisized vacuoles up to 20 um (spongiosis).
MORPHOLOGIC DIAGNOSIS: Cerebrum: Encephalitis, histiocytic, multifocal and perivascular, mild, with multinucleated giant cells, 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
· Small (80 – 100nm diameter), enveloped, single-stranded RNA, in the family Retroviridae, subfamily Lentiviridae
· Like other retrovirus, SIV contains env, pol, and gag genes
· Serotype identification is based on species infected (SIVmac = Macaca
· There are several species of wild Old World nonhuman primates that harbor a lentivirus that evolved with that particular host; these natural hosts (African green monkey – SIVagm) have a persistent viral infection that does not cause overt disease; but, introduction into an aberrant host (rhesus macaques) will cause an AIDS-like disease
· SIVmac in rhesus monkeys in the wild in Asia has not been identified, but 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
· Monocytes/macrophages and CD4+ lymphocytes are the target cells for the virus
· Midfrontal cortical gray matter, caudate and hippocampal neurons are at greatest risk for damage, followed by deep cerebellar gray matter and basal ganglia
· 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:
o Cytokines such as tumor necrosis factor (TNF) and interleukins (eg IL-1, IL-6)
o Other potentially damaging chemicals such as nitric oxide, superoxide anion, hydroxyl radicals, peroxides, and quinolates
· Simian lentiviral infection induces the following:
o Elevated endothelial vascular cell adhesion molecule-1 (VCAM-1)
o Elevated endothelial and/or perivascular macrophage expression of chemokines (MIP-1alpha, MIP-1beta, RANTES)
o Over-expression of chemokine receptors (CCR3, CCR5, CXCR3, CXCR4) on virus infected macrophages, multinucleated giant cells, and lymphocytes
§ Increased numbers of infected monocytes/macrophages migrating across the blood-brain barrier > release neurotoxic cytokines > neuronal injury and death
§ Chemokine receptor on neurons (CCR5) allow direct interaction with virus > virus alters cell signaling > abnormal neuronal cellular function
· In both normal and SIV infected macaques, there is constitutive expression of chemokine receptors on pyramidal hippocampal and cortical neurons, microglia, and astrocytes
TYPICAL CLINICAL FINDINGS:
· Initially: Inguinal rash, generalized lymphadenopathy, diarrhea
· Later: Wasting syndrome, chronic enteritis and opportunistic infections (viral, bacterial, protozoal, metazoal and fungal) secondary to lymphoid depletion
· Severity of neurologic signs depends on species, viral strain, and viral RNA concentrations in various brain regions; there may or may not be cognitive impairment
TYPICAL GROSS FINDINGS:
o Increased amount of subdural blood-tinged CSF
o Congested brain surface
o Decreased thickness of cortical gyri and sulci (atrophy)
· Lesions independent of immunosuppression in other organs
o Skin: Disseminated cutaneous eruptions (rash)
o Gastrointestinal tract: Fulminant necrohemorrhagic gastroenteritis
o Cardiopulmonary: Interstitial pneumonia, +/- vessel hypertrophy thrombosis and infarction
o Nervous: Listed above
o Lymphoid: A pattern from lymphoid hyperplasia (early) to follicular involution (late)
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· Lesions independent of immunosuppression (direct actions)
o Skin: Exanthema with non-descript superficial and perivascular lymphocytic dermatitis with variable swelling and degeneration of the epidermis
o Gastrointestinal tract: Some strains produce a fulminant necrohemorrhagic enteritis
o 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
§ Perivascular cuffing by macrophages, multinucleated giant cells, and fewer lymphocytes, especially in the white matter; gliosis
§ Granulomatous encephalitis: Macrophages, multinucleated giant cells, microglial nodules
o 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: Cytomegalovirus, adenovirus, papovavirus, Pneumocystis carinii, Mycobacterium avium complex, Cryptosporidium sp., Cryptococcus neoformans, Toxoplasma gondii, and Candida albicans (described elsewhere)
· Lentiviral particles: Membrane bound cytoplasmic vacuoles in macrophages and syncytial cells
· Multinucleated giant cells may have myelin inclusions
ADDITIONAL DIAGNOSTIC TESTS:
o CD163 – differentiates perivascular macrophages from resident brain macrophages (parenchymal microglia)
o Elevated endothelial VCAM-1, chemokines (C-C or C-X-C) and chemokine receptors (associated with SIV encephalitis)
· Macaques are natural hosts for 3 exogenous retroviruses that may cause immunosuppression or lymphoproliferative disease:
o 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
o 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
o Simian foamy virus (SFV): Retrovirus, subgroup spumavirus mostly non-pathogenic, infects wide variety of tissues and potential candidate for a viral vector for gene therapy
Causes of encephalitis in non-human primates:
o Toxoplasma gondii: Cysts smaller than E. cuniculi with crescent shaped tachyzoites
o Balamuthia mandrillaris (amoeba): Acute suppurative meningoencephalitis, microgranulomas, vasculitits, gram positive organisms
o Acanthamoeba sp.: Multifocal to coalescing necrotizing neutrophilic meningoecephaltis and pneumonitis with trophozoites and cysts
o Encephalitozoon cuniculi: Granulomatous encephalitis or meningoencephalitis; Gram positive oval rods that are also Giemsa positive
o Trypanosoma cruzi: Similar to T. gondii but contain a kinetoplast
o Acute measles encephalitis (morbillivirus): Progressive gliosis, demyelination and neuronal loss with intranuclear inclusions and a nonsuppurative, perivascular meningoencephalitis
o 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
o Polyomavirus: Progressive multifocal leukoencephalopathy with demyelination; bizarre shaped astrocytes and oligodendroglia with enlarged nuclei and intranuclear inclusion bodies
o SV40 (Papovavirus): Meningoencephalitis without demyelination; virus in astrocytes instead of oligodendrocytes
o Herpes simplex virus (H. simiae – B virus; Macacine herpesvirus 1): Necrotizing encephalomyelitis, intranuclear inclusion bodies, syncytial cells
o Streptococcus pneumoniae: Severe fibrinopurulent leptomeningitis, markedly congested meningeal vasculature, necrotizing vasculitis with thrombosis in the meninges, gray matter and white matter
o Mycobacterium tuberculosis and M. bovis: Multifocal cerebral granulomas with rare acid fast positive bacilli
o Klebsiella pneumoniae: Meningitis, gram negative bacteria with prominent capsules
o Listeria monocytogenes: Purulent meningoencephalitis, gram positive rods
o Cryptococcus neoformans: Meningoencephalitis, narrow based single budding, and granulomatous changes
· Other immunodeficiency viruses: Human (HIV), feline (FIV), and bovine (BIV)
· Other lentiviruses: Equine infectious anemia (EIA), Caprine arthritis and encephalitis virus (CAEV), Visna-Maedi
1. Bissel SJ, Wang G, Bonneh-Barkay D, Starkey A, Trichel AM, Murphey-Corb M, Wiley CA. Systemic and brain macrophage infections in relation to the development of simian immunodeficiency virus encephalitis. J Virol. 2008;82(10):5031-5042.
2. Ellison D, Chimelli L, Harding B, et al. Neuropathology. Barcelona, Spain: Mosby International Ltd; 1998:13.7-13.
3. 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. 2nd ed. San Diego, CA: Academic Press; 2012:759-762.
4. Johnson RP. How HIV guts the immune system. N Engl J Med. 2008;358(21):2287-2289.
5. Kaliyaperumal S, Dang X, et al. Frequent infection of neurons by SV40 virus in SIV-infected macaque monkeys with progressive multifocal leukoencephalopathy and meningoencephalitis. Am J Pathol. 2013; 183(6):1910-1917.
6. Mansfield K, King N. Viral diseases. In: Bennett BT, Abee CR, Henrickson R, eds. Nonhuman Primates in Biomedical Research: Diseases. San Diego, CA: Academic Press; 1998:84-86.
7. Nowlin BT, Burdo TH, et al. SIV encephalitis are composed of CD163(+) macrophages present in the central nervous system during early SIV infection and SIV-positive macrophages recruited terminally with AIDS. Am J Pathol. 2015; 186(6):1649-1665.
8. Persidsky Y. Insights into end-organ injury in HIV infection: Dynamics of monocyte trafficking to the brain in SIV encephalitis. Am J Pathol. 2015; 185(6):1548-1551.
9. Xing HQ, Moritoyo T, Mori K, Sugimoto C, Ono F, Izumo S. Expression of proinflammatory cytokines and its relationship with virus infection in the brain of macaques inoculated with macrophage-tropic simian immunodeficiency virus. Neuropathology. 2009; 29(1):13-19.