Signalment:  

5-year-old, male, intact Rhesus macaque (Macaca mulatta).This macaque presented for necropsy at the end of an experiment investigating vaccine candidates for Simian Immunodeficiency Virus (SIV). The animal had been losing weight for the previous four months but was clinically unremarkable. Experimental manipulation included biweekly phlebotomy. Two years prior to necropsy, the animal had been vaccinated with an experimental vaccine and seven months prior to necropsy had been inoculated with SIVmac251.

Gross Description:  

The animal was thin with few fat reserves and the right atrium was moderately dilated. There was a moderate amount of serous pericardial effusion. The lungs were firm and failed to deflate upon opening the chest cavity.

Histopathologic Description:

Labial mucosa: Multifocally submucosal nerves and hair follicles are partially to completely effaced by large aggregates of degenerate and non-degenerate neutrophils admixed with fewer histiocytes, lymphocytes and necrotic cellular debris. Frequently, histiocytes within the inflammatory infiltrate are enlarged and contain large, eosinophilic, intranuclear, round to ovoid, 10-20 μm diameter inclusion bodies and smaller eosinophilic intracytoplasmic inclusion bodies. Nerve fibers are completely effaced by the infiltrate and there is a dual loss of the myelin sheath and the axon. Inflammatory cells frequently infiltrate into the surrounding musculature. In these areas myofibers are variably swollen, hypereosinophilic and degenerate with sarcoplasmic vacuolation and loss of cross striations. Several large hair follicles are surrounded by a moderate amount of fibrosis and a similar neutrophilic and histiocytic infiltrate with frequent intracytoplasmic and rare intranuclear inclusion bodies. The inflammatory cells are especially abundant in the perifollicular tissue, but also are present through all layers of the hair follicle and are associated with moderate perifollicular hemorrhage and congestion. 

Morphologic Diagnosis:  

1. Labial mucosa and haired skin: Severe, multifocal, subacute neutrophilic neuritis with cytomegaly and intrahistiocytic, intranuclear and intracytoplasmic herpetic inclusions (Cowdry type A).
2. Labial mucosa and haired skin: Severe, multifocal, subacute to chronic neutrophilic folliculitis with perifollicular fibrosis, cytomegaly, and intrahistiocytic, intranuclear and intracytoplasmic herpetic inclusions (Cowdry type A).

Lab Results:  

Serial chemistry profiles were unremarkable.

Condition:  

Cytomegalovirus

Contributor Comment:  

Simian immunodeficiency virus (SIV) was first isolated in rhesus macaques at the New England Primate Research Center in 1985 and since then numerous strains of SIV which are endemic to different species of African monkeys have been identified. When these viruses are transmitted to Asian species they induce a disease similar to human AIDS, making the rhesus macaque model of SIV infection uniquely suited to studying HIV/AIDS pathogenesis.(2)

Common clinical and pathologic findings in SIV infected rhesus macaques include lymphadenopathy/lymphoma, chronic diarrhea and wasting, giant cell disease, pulmonary arteriopathy, viral associated dermatitis, and a wide spectrum of opportunistic infections. The most common opportunistic infectious agents in rhesus macaques progressing to AIDS include Pneumocystis carinii, Mycobacterium avium complex, Trichomonas sp., cytomegalovirus, adenovirus, Cryptosporidium, SV-40, Candida sp., and rhesus lymphocryptovirus.(10) Additionally, infections with Enterocytozoon bienusi, Entamoeba, Giardia and various alphaherpes viruses are also seen regularly. 

Cytomegaloviruses (CMV) are host-specific beta-herpesviruses that frequently establish latent infections in both rhesus macaques and humans. In rhesus macaques, CMV seroprevalence approaches 100% by one year of age but there are generally no clinical or pathologic findings associated with infection in otherwise healthy individuals.(3,11) Transmission is thought to be through contact with virus shed in urine, saliva, and genital secretions which is similar to findings in humans. Unlike in humans, vertical transmission has not been documented, most likely due to near 100% seroprevalence with resultant high maternal antibodies and fetal protection. 

With immune suppression, as occurs with AIDS, latent CMV becomes reactivated. It is the most common viral opportunistic infection identified and among the most common opportunistic infections overall in both rhesus macaques and man with isolation from the retina, gastrointestinal tract, lungs, and adrenal gland common in humans and gastrointestinal tract, lungs, central nervous system, liver and lymph nodes in macaques.(4,5)

Common gross pathologic features of cytomegalovirus infection depend on the organ involved. A common finding at the NEPRC is gastrointestinal pseudotumors which present as raised, red lesions multifocally throughout the small intestine.(7) Less common gross findings include multifocal interstitial pneumonia, necrotizing orchitis, and gastrointestinal ulceration. Histologically, lesions are frequently characterized by intense neutrophilic infiltrates admixed with fewer lymphocytes and plasma cells. Scattered throughout these areas there are frequently large intranuclear inclusion bodies, so-called owls eye cells and also smaller intracytoplasmic inclusion bodies. 

Unfortunately, these cells are not always present and as many as one half of infected animals may show varying degrees of pathology without characteristic inclusion bodies making immunohistochemistry important for definitive diagnosis of suspected cases. In fact, immunohistochemistry has shown that some animals with no underlying pathology have viral reactivation in multiple organs.(5)

In this case, the CMV-associated neuritis and folliculitis of the labial mucosa is quite striking. While not a common finding with CMV reactivation, neuritis is seen occasionally in rhesus macaques at the NEPRC and is most commonly seen in the labial and buccal mucosa. In humans, CMV optic neuritis and retinitis is a common finding. We have not previously identified folliculitis and this is an uncommon finding in humans as well. 

JPC Diagnosis:  

1. Haired skin and mucocutaneous junction, lip: Polyneuritis, suppurative, acute, moderate, with axonal degeneration and intranuclear and intracytoplasmic eosinophilic and amphophilic inclusion bodies.
2. Haired skin and mucocutaneous junction, lip: Epidermal hyperplasia, focally extensive, moderate, with hyperkeratosis.

Conference Comment:  

The contributor provides an excellent synopsis of a unique presentation of CMV infection in this case, and conference participants used the discussion as a starting point to review the concepts of latency and recrudescence in herpesviral infection. Immunocompetent, asymptomatically-infected rhesus macaques expend substantial immunological resources to maintain a stable virus-host relationship, and possess high numbers of circulating CD4+ and CD8+ rhesus CMV-specific T cells in peripheral blood.(11) Like other herpesviruses, human CMV evades the immune system by downregulating MHC class I and II molecules, and producing homologues of MHC class I molecules, IL-10, and tumor necrosis factor (TNF) receptor.(6) Rhesus CMV has also been shown to encode inhibitors of natural killer cell function and class I MHC assembly and transportation, and homologues of cellular IL-10, a viral inhibitor of caspase activation, and a viral inhibitor of apoptosis.(11) Participants briefly reviewed other cytomegaloviruses of importance in veterinary medicine, which are summarized in the table below:(1,8,9)

Cytomegaloviruses in Veterinary Species
Name	Virus Subfamily	Species Affected	Summary
Simian CMV (includes Rhesus CMV)	Betaherpesvirus	Rhesus macaque; other NHP have host-specific CMV	Seroprevalence nearly 100% in rhesus macaques; clinical disease occurs only with immunosuppression (SIV) or experimental manipulation
Caviid herpesvirus	Betaherpesvirus	Guinea pig	Subclinical infection is common; useful model of human CMV; typical "owls eye" inclusions; targets are salivary gland, kidney, and liver
Murine CMV (Murid herpesvirus 1)	Betaherpesvirus	Mouse	BALB/c and A strain mice are susceptible; B6, B10, CBA, and C3H mice are resistant; disease occurs in immunocompromised mice; typical lesions are in salivary glands; persistent infections may cause immune complex glomerulitis
Rat CMV	Betaherpesvirus	Rat	Common in wild rats; nonexistent in laboratory rats; typical lesions in salivary and lacrimal glands with intranuclear and intracytoplasmic inclusions in ductal epithelium
Bovine herpesvirus 4	Gammaherpesvirus	Ox	Associated with "epivag" (i.e. vaginitis, salpingitis, oophoritis, or epidiymitis), pneumonia, enteritis, metritis, mammillitis, and abortion
Suid herpesvirus 2	Betaherpesvirus	Pig	Causes inclusion body rhinitis in neonates; infection in pregnant sows results in small litters, mummification, stillborith, or weak, premature offspring; typical cytomegaloviral inclusions in nasal mucosa, lung, or kidney, but not seen in the placenta
Equid herpesvirus 2	Gammaherpesvirus	Horse	Clinical significance unknown; has been identified in few cases of bronchointerstitial pneumonia in foals

The contributors observation of inflammation involving the hair follicles was also discussed. Most conference participants interpreted the folliculitis as a secondary extension of the neurocentric inflammation into the sinus hairs, rather than primary folliculitis due to viral infection of hair follicles. When present, inflammation of the hair follicles was generally confined to well-innervated sinus hairs, and in less severely affected follicles, the inflammatory cells appeared to extend from the peripheral nerve into the stroma surrounding the adnexa. 

References:

1. Ho M: The history of cytomegalovirus and its diseases. Med Microbiol Immunol 197:65-73, 2008
2. Jellinger KA, Setinek U, Drlicek M, Bohm G, Steurer A, Lintner F: Neuropathology and general autopsy findings in AIDS during the last 15 years. Acta Neuropathol 100 :213-220, 2000
3. Kuhn EM, Stolte N, Matz-Rensing K, Mach M, Stahl-Henning C, Hunsmann G, Kaup FJ: Immunohistochemical studies of productive rhesus cytomegalovirus infection in rhesus monkeys (Macaca mulatta) infected with simian immunodeficiency virus. Vet Pathol 36:51-56, 1999
     a. Geretti AM: Simian immunodeficiency virus as a model of human HIV disease. Rev Med Virol 9:57-67, 1999
     b. Caswell JL, Williams KJ: Respiratory system. In: Jubb, Kennedy, and Palmers Pathology of Domestic Animals, ed. Maxie MG, 5th ed., vol. 2, p. 569. Elsevier Saunders, Philadelphia, PA, 2007
4. McAdam AJ, Sharpe AH: Infectious diseases. In: Robbins and Cotran Pathologic Basis of Disease, eds. Kumar V, Abbas AK, Fausto N, Aster JC, 8th ed., pp. 353-355. Saunders Elsevier, Philadelphia, PA, 2010
5. Mohan H, Bal A, Garg S, Dalal U: Cytomegalovirus-associated pseudotumor simulating gastric malignancy in acquired immunodeficiency syndrome: a case report with review of literature. Jpn J Infect Dis 60:134-136, 2007
6. Percy DH, Barthold SW: Pathology of Laboratory Rodents and Rabbits, 3rd ed., pp. 19-21, 127, 221-222. Blackwell Publishing, Ames, IA, 2007
7. Schlafer DH, Miller RB: Female genital system. In: Jubb, Kennedy, and Palmers Pathology of Domestic Animals, ed. Maxie MG, 5th ed., vol. 3, pp. 528-529, 531-532. Elsevier Saunders, Philadelphia, PA, 2007
8. Simon MA, Chalifoux LV, Ringler DJ: Pathologic features of SIV-induced disease and the association of macrophage infection with disease evolution. AIDS Res Hum Retroviruses 8:327-337, 1992
9. Yue Y, Barry PA: Rhesus cytomegalovirus a nonhuman primate model for the study of human cytomegalovirus. Adv Virus Res 72:207-226, 2008

Click the slide to view.

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1-1. Lip, peripheral nerve

1-2. Lip, peripheral nerve

1-3. Lip

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