Signalment:  

6-year-old male rhesus macaque (Macaca mulatta). This macaque was inoculated intravascularly with SHIV in April 2010. The macaque tested negative for Herpes B, measles virus, SRV, STLV-1, and SIV one year prior to experimental infection. The macaque was relatively healthy for approximately 2 years post-infection, but several months prior to necropsy developed a nasal discharge and was treated with antibiotics over this period. The macaque became acutely hypoactive and lethargic and euthanasia was performed.

Gross Description:  

The macaque was somewhat thin but relatively well muscled and contained a small amount of body fat. Within the pinna of the left ear, there was a focal area of ulceration with a superficial scab measuring approximately 1.5 cm in diameter. There was a focal slightly elevated tan-white lesion measuring approximately 1 cm in greatest dimension on the tip of the left side of the tongue. The remainder of the tongue and oral cavity appeared normal. 

The mesenteric lymph node was severely enlarged and measured 5.0 x 3.5 x 2.0 cm, and was tan to white on cut surface. A focal tan-white lesion was present within the jejunum with prominent thickening of the wall over a length of 4.5 cm. The colonic and pancreatic lymph nodes were moderately enlarged. The spleen was mildly enlarged and there were multiple nodules within the parenchyma which were irregular, tan-white and up to 1.5 cm in diameter. The wall of the gallbladder was moderately to severely thickened and was white to tan. These lesions were consistent with lymphoma. 

The heart, kidneys, stomach, duodenum, ileum, cecum, colon and testes appeared normal. Several adhesions were present between the right caudal lung lobe and thoracic wall. The lungs otherwise appeared grossly normal.

Histopathologic Description:

The submitted slide is a section from the left ear pinna. The epidermis is focally ulcerated with an overlying serocellular crust, comprised primarily of degenerative neutrophils. The epidermis at the lateral margins of the lesion is irregular, with disarray and ballooning of epithelial cells, admixed with degenerative neutrophils. Many epithelial cells along the margin have enlarged nuclei with marginated chromatin and prominent amphophilic intranuclear inclusion bodies. Several syncytial cells are evident, containing intranuclear inclusions. Some of the adjacent sebaceous glands have similarly affected epithelium with cells containing prominent intranuclear inclusion bodies. 

Examination of the tongue (not submitted) revealed an acute focal ulcerative glossitis with the margins of the lesion containing epithelial cells with prominent amphophilic intranuclear inclusion bodies. Transmission electron microscopy from a section of tongue revealed intranuclear icosahedral viral nucleocapsid particles measuring approximately 100 nm, and enveloped particles approximately 160 nm in diameter in the cytoplasm, consistent with herpesviral particles. 

Other significant findings in this case included lymphoblastic lymphoma affecting the spleen, jejunum, gall bladder, adrenal gland, and mesenteric, perisplenic, pancreatic and colonic lymph nodes. Additionally, there was a granulomatous colitis and lymphadenitis affecting a portion of the colon and associated lymph nodes due to mycobacterial infection, with large numbers of acid fast bacilli evident in macrophages in the affected tissue. Mild to moderate multifocal interstitial pneumonia and fibrosis were evident in the lung. 

Morphologic Diagnosis:  

External ear, otitis externa, acute, focal, ulcerative, with intranuclear inclusion bodies, consistent with alpha herpesvirus.

Lab Results:  

Total lymphocyte counts averaged 1145/ uL over the last six months of life. CD4 counts were less than 200/uL over the same period. The macaque maintained a high level of viremia for SHIV during this period.

Condition:  

Macacine herpesvirus-1

Contributor Comment:  

This macaque developed several disease conditions related to immunosuppression from experimental infection with SHIV. The principal presenting signs were upper respiratory and were likely related to the findings of pulmonary fibrosis and multifocal interstitial pneumonia. The macaque had lymphoma affecting multiple organs. Additionally, there was granulomatous colitis multifocally due to infection with mycobacteria. The findings of herpetic lesions involving the tip of the tongue and the left ear also reflect the ongoing immunosuppressive state in this macaque. The external pinna is an unusual location for active herpesviral infection, with the lingual lesion being more typical. No other lesions were noted systemically due to herpesviral infection. While the herpesviral infection is likely due to macacine herpesvirus-1 in this case, the possibility of infection with herpes simplex virus-1 cannot be ruled out. This macaque had tested previously negative by serology for herpes B and this may represent a false negative result. While the macaque may have become infected subsequent to experimental SHIV inoculation, this is less likely as these macaques were singly housed following inoculation. 

Macacine herpesvirus-1, previously known as Cercopithecine herpesvirus-1, Herpesvirus simiae and Herpes B virus is a common alpha herpesvirus infection affecting Old World macaques. It has been documented in rhesus macaques (Macaca mulatta), cynomolgus macaques (M. fascicularis), stumptail macaques (M. artoides), pigtailed macaques (M. nemestrina), Japanese macaques (M. fuscata), bonnet macaques (M. radiata) and Taiwan macaques (M. cyclopis). Natural infection in macaques is usually asymptomatic, with localized mucosal lesions occurring infrequently. Transmission is horizontal between macaques with most animals acquiring the infection by 2-4 years of age. Lesions when present typically involve the oral and gingival mucosa, tongue and conjunctiva. Genital lesions are generally not observed.(5) Infection of New World monkeys, while uncommon, is also possible. Asymptomatic natural infection with macacine herpesvirus-1 has been documented in a colony of brown capuchin monkeys (Cebus apella).(3)

Macacine herpesvirus-1 has typical morphology for alpha-herpesviruses and is composed of double stranded DNA, with a 40 nm core, icosahedral nucleocapsid approximately 100 nm in diameter and enveloped particles of 160-180 nm in the infected cell cytoplasm. Host cell infection occurs by fusion of viral envelope with host cell plasma membranes, penetration of nuclear pores by viral capsids with release of viral DNA in the nucleus, leading to viral replication.(6)

Transmission typically occurs via exposure of oral, ocular or genital mucous membranes from an infected animal shedding virus most commonly in saliva. The virus replicates locally, enters sensory nerves and is transmitted intra-axonally where it can remain latent in sensory ganglia, protected from host immune responses. Reactivation can occur periodically from the latent state, with virus being transported down axons to mucosal tissues. The majority of reactivated infections are asymptomatic. Virus carriers generally have a low rate of shedding, however, stress associated with transportation, changes in social groupings and immunosuppression can lead to reactivation and viral shedding.(4)

While generally not a significant clinical disease entity for immunocompetent macaques, cases of systemic infection have been documented in cynomolgus macaques causing necrosis of lung, liver, spleen, pancreas, and adrenal glands.(2,7) In one of these cases infection with Simian retrovirus type D was noted as the likely cause of immunosuppression leading to pathogenic herpesvirus infection.(2)

Macacine herpesvirus is an extremely important zoonotic agent. Human exposure to an infected macaque shedding virus can result in a highly pathogenic infection leading to CNS involvement and a fatality rate greater than 70% in individuals who are not treated aggressively with antiviral drugs.(1,4) Universal precautions with appropriate PPE are required when working with nonhuman primates. Any exposure by scratch, bite, needle stick injury or any other exposure of mucous membranes or an open skin wound require immediate attention and consultation with occupational medical specialists. 

JPC Diagnosis:  

Haired skin, pinna: Dermatitis, necrotizing, multifocal, severe, with folliculitis, furunculosis, and numerous intraepithelial intranuclear viral inclusions and syncytia.

Conference Comment:  

The contributor has provided an excellent review of macacine herpesvirus-1. In addition to the section of ulcerated pinna, the contributor/moderator provided conference participants with the opportunity to examine multiple tissues from this animal, both microscopically and grossly (via photographs). Lesions in the tongue were similar to those described in the pinna, with focally extensive glossal ulceration, a marked neutrophilic infiltrate, large eosinophilic intra-nuclear inclusion bodies within epithelial cells and occasional viral syncytia. Transmission electron microscopy of the tongue was also consistent with α-herpesviral infection (see contributors histopathologic description). The spleen, liver, gallbladder, multiple lymph nodes and a focal area of the jejunum were grossly thickened/enlarged. Microscopically, these tissues were infiltrated by a monomorphic population of mononuclear cells with large nuclei and prominent nucleoli, interpreted as disseminated lymphoblastic lymphoma. Neoplastic lymphocytes demonstrated strong cytoplasmic immunoreactivity for anti-CD79a, suggesting B-cell origin, although there were scattered CD3-positive T-cells within the neoplasm. There was also marked granulomatous lymphadenitis and colitis. Several mesenteric lymph nodes and sections of colon were effaced by numerous epithelioid macrophages, with abundant intra-histiocytic acid-fast bacilli, consistent with Mycobacterium avium. Interestingly, despite this considerable microscopic evidence of mycobacteriosis, PCR for Mycobacteria spp. was negative. 

Overall, this rhesus macaque had lymphoma, α-herpesviral glossitis and otitis externa, granulomatous lymphadenitis/colitis (likely secondary to M. avium) and alveolitis, interstitial pneumonia and fibrosis. 

References:

1. Bailey CC, Miller AD. Ulcerative cheilitis in a rhesus macaque. Vet. Pathol. 2012;49(2):412-415.

2. Carlson CS, OSullivan MG, Jayo MJ, et al. Fatal disseminated cercopithecine herpesvirus 1 (herpes B infection in cynomolgus monkeys (Macaca fascicularis). Vet. Pathol. 1997;34(5):405-14.

3. Coulibaly C, Hack R, Seidl J, et al. A natural asymptomatic herpes B virus infection in a colony of laboratory brown capuchin monkeys (Cebus apella). Lab. Anim. 2004;38(4):432-8.

4. Elmore D, Eberle R. Monkey B virus (Cercopithecine herpesvirus 1). Comp. Med. 2008;58(1):11-21.

5. Huff JL, Barry PA. B virus (Cercopithecine herpesvirus 1) infection in humans and macaques: potential for zoonotic disease. Emerg. Infect. Dis. 2003;9(2): 246-50.

6. Jainkittivong A, Langlais RP. Herpes B virus infection. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 1998;85(4):399-403.

7. Simon MA, Daniel MD, Lee-Parritz D, et al. Disseminated B virus infection in a cynomolgus monkey. Lab. Anim. Sci. 1993;43(6):545-50.

Click the slide to view.

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4-1. Pinna

4-2. Tongue

4-3. Mesenteric lymph nodes

4-4. Pinna

4-5. Pinna

4-6. Pinna

4-7. Pinna

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