October 2023

P-V19

Signalment (JPC# 2237950): Ten-year-old female rhesus monkey

HISTORY: Tissue from a rhesus monkey that was inoculated intramuscularly with an infectious agent as a part of a research project. Multifocally the lungs were wet and tan to red. Lymphoid tissue and thymus were markedly reduced in size.

HISTOPATHOLOGIC DESCRIPTION: Lung: There is mild to moderate patchy to diffuse consolidation affecting approximately 90% of the section as well as multifocal alveolar emphysema and perivascular edema. Diffusely, alveolar septa are mildly to moderately expanded up to 4x normal by macrophages, fewer lymphocytes and plasma cells, eosinophilic beaded fibrillar material (fibrin), and homogenous eosinophilic fluid (edema). There is multifocal necrosis and loss of type I pneumocytes with replacement by cuboidal epithelial cells (type II pneumocyte hyperplasia). Many alveolar lumina contain 1-2 multinucleated giant syncytial cells that are up to 90 µm in diameter and have abundant granular, eosinophilic cytoplasm and multiple nuclei (up to 25 nuclei). Syncytial cells are admixed with low numbers of alveolar macrophages, lymphocytes, plasma cells, fewer neutrophils, fibrin, and edema. Alveolar lumina less frequently and multifocally contain eosinophilic flocculent aggregates of extracellular and intrahistiocytic fungal trophic forms that are round, 1-2 µm in diameter, have a thin eosinophilic cell wall, and clear interior. Bronchiolar epithelium is occasionally lost or attenuated, and there is occasional mild goblet cell hyperplasia. Bronchiolar lumina contain small amounts of an exudate composed of mucin, sloughed epithelial cells, fibrin, and edema. The tunica adventitia and perivascular interstitium is mildly expanded by edema with ectatic lymphatics and contains a few multifocal aggregates of lymphocytes and plasma cells.

MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, interstitial, lymphohistiocytic, chronic, diffuse, moderate, with viral syncytial cells, perivascular edema, and fungal trophic forms consistent with Pneumocystis spp., rhesus monkey (Macaca mulatta), nonhuman primate.

ETIOLOGIC DIAGNOSIS: Simian lentiviral pneumonia; pulmonary pneumocystosis (see P-F07)

CAUSE: Simian Immunodeficiency virus (SIV)

SYNONYMS: Giant cell pneumonia

GENERAL DISCUSSION:

Simian immunodeficiency viruses (SIV) are a group of enveloped ssRNA virus from family Retroviridae and subfamily Lentiviridae that are indigenous to African nonhuman primates
Retroviruses include two subfamilies:
1. Orthoretrovirinae: Betaretrovirus, Deltaretrovirus, Gammaretrovirus, and Lentivirus
2. Spumaretrovirinae: Spumavirus
There are seven major lineages of related viruses that occur naturally in several species of old world primates
1. Viral strains given a three-letter suffix indicating the common name of the species from which they were originally isolated (e.g., SIVcpz from chimpanzees)
2. SHIV is a chimera that includes the HIV envelope with an SIV back bone
Natural hosts are persistently infected, but are usually asymptomatic (may rarely develop SAIDS, see below); disease generally caused when transferred to a different species
1. Asian macaques (e.g., rhesus macaque, cynomolgus macaque) are highly susceptible to SIV infection and develop fatal immunodeficiency (SAIDS)
2. Natural disease in New World nonhuman primates has not been identified
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
Very similar to HIV in humans; is an important research model (pathogenesis, vaccination, therapy) for AIDS in humans
Common opportunistic infectious agents include Pneumocystis spp, Mycobacterium spp, Cryptosporidium spp., Cryptococcus neoformans, Candida albicans, Plasmodium spp.; cytomegalovirus (CMV), adenovirus, papovavirus, lymphocryptovirus (occasionally resulting in non-Hodgkin lymphomas (NHL))

PATHOGENESIS:

Transmission
1. In natural hosts, there is both horizontal and vertical transmission with rapid spread
2. Sexual and wounding are both significant transmission modes in the wild
Marked tropism for CD4+ cells: Helper T cells, also monocytes, macrophages, and dendritic cells
1. Interaction between viral protein gp120 and host cell CD4 and CCR5 chemokine receptor
2. The virus enters cytoplasm à Viral ssRNA transcribed to DNA (using reverse transcriptase à Integrated into host genome à Transcription creates progeny viruses à Budding, release from cells à Infect other cells
  - CD4+ cell depletion likely due to multiple causes (viral lysis, apoptosis, etc.)
3. In African macaques: Depletion of CD4+ T-cells at mucosal sites
4. In Asian macaques: Often progressive loss of CD4+ T cells and onset of SAIDS with severe immune dysfunction, lymph node and spleen depletion, lymphopenia, (typically) B-cell lymphoma, and death due to opportunistic infections
Giant cell disease with large, multinucleated syncytia (CD68+, macrophage lineage) in multiple tissues (lymphoid, liver, lung, GI, CNS)
1. Due to expression of viral env glycoproteins à Fusion with adjacent CD4+ cells
Other primary viral lesions with unique pathogeneses:
1. CNS: Viral meningoencephalitis due to increased expression of VCAM-1 on endothelium within the brain (See N-V14)
2. GI: Rapid and marked T-cell loss à Compromise of mucosal immunity, loss of intestinal epithelial cells à Intestinal mucosal compromise
3. Skin: CD8+ CTLs directed at epidermal Langerhans cells
4. Cardiopulmonary: Vessels infiltrated by CD68+ macrophages à Arteriopathy with thrombosis, consolidation, and infarction

TYPICAL CLINICAL FINDINGS:

Within first weeks of infection: Maculopapular skin rash on sparsely haired portions of the body, lymphadenopathy
Chronic diarrhea and wasting are the most common clinical signs, also peripheral neuropathy
1. Various opportunistic infections due to loss of CD4 T-cells

TYPICAL GROSS FINDINGS:

Cardiopulmonary: Interstitial pneumonia, +/- proliferative arteriopathy, right atrial and pulmonary thrombosis, and infarction

Skin: Disseminated cutaneous eruptions (rash) of trunk, groin, medial thighs, and face
Gastrointestinal tract: Enteritis; +/- fulminant necrohemorrhagic gastroenteritis
Nervous: Subdural blood-tinged CSF with congestion; cortical atrophy

Lymphoid: Varies from lymphoid hyperplasia (lymphadenomegaly, splenomegaly) (early) to follicular involution (late)

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Cardiopulmonary:
1. Interstitial pneumonia with syncytial cells
2. Extensive medial and intimal smooth muscle proliferation of medium and large sized pulmonary arteries, and often associated with thrombosis and infarction of pulmonary parenchyma
Skin: Superficial and perivascular lymphocytic dermatitis with variable swelling and degeneration of the epidermis
GI: Villous blunting and atrophy, crypt hyperplasia, lymphocyte loss (CD4+ T-cells)
CNS: Granulomatous/giant cell encephalitis affecting grey and white matter of brain and spinal cord, myelin degeneration/loss, glial nodules, spongiosis, neuronal necrosis
Lymphoid: Six distinct patterns (not mutually exclusive) (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

ADDITIONAL DIAGNOSTIC TESTS:

Immunohistochemistry: Giant cells are CD68+ (macrophage/monocyte lineage)
PCR
in situ hybridization
Transmission electron microscopy

DIFFERENTIAL DIAGNOSIS:

Pneumonia in macaques:

Human measles virus (P-V02, Paramyxoviridae: Morbillivirus) – Bronchointerstitial pneumonia with syncytial giant cells that have intracytoplasmic AND intranuclear inclusion bodies, and orientation of inflammation around small bronchioles; multinucleated giant cells in skin, lymph nodes, lung
Cytomegalovirus/Beta herpesvirus (P-V12, Macacine herpesvirus 3): May occur secondary to SIV infection; cytomegaly, very large intranuclear inclusions (INIB) and occasional intracytoplasmic inclusions (ICIB)
Non-human primate herpesviruses:

Macacine herpes-1 (Alphaherpesvirus): Necrotizing pneumonia with INIBs, syncytial cells
Simian varicella virus-neurotropic (Alphaherpesvirus): Papulovesicular rash at mucosa with Cowdry type A INIBs in perivesicular cells
Herpes simplex (Alphaherpesvirus): Syncytial cells with INIBs

Poxvirus: Fibrinonecrotic pneumonia with ICIBs (Guarnieri bodies)
Adenovirus: Large, deeply basophilic, and “smudgy” intranuclear inclusions that are not surrounded by a clear halo (often in pancreas)
Simian virus 40 (Polyomavirus): Type II pneumocyte hyperplasia; pneumocytes with prominent basophilic INIBs; bronchial and bronchiolar epithelium not affected

COMPARATIVE PATHOLOGY:

SIV is not oncogenic but lymphoid neoplasms are common and associated with rhesus lymphocryptoviruses

Other Simian retroviruses:

Simian retrovirus (SRV) (formerly known as Type D retroviruses): Betaretrovirus, the most important cause of immunosuppression in macaques, and results in broad spectrum of disease from subclinical to rapidly fatal immunosuppressive disease; can lead to can cause an immunodeficiency syndrome: Simian AIDS (SAIDS)
Simian T-lymphotropic viruses or simian T-cell leukemia viruses (STLVs): A Deltaretrovirus similar to bovine leukemia viruses; most are asympomatic, small proportion develop T-cell lymphoma or lymphoproliferative disease
Simian foamy virus (SFV): A spumavirus subgroup. Mostly non-pathogenic, infects wide variety of tissues and potential candidate for a viral vector for gene therapy

Other lentiviruses:

Domestic cats and cheetahs: Feline immunodeficiency virus
Cattle: Bovine immunodeficiency (or immunodeficiency-like) virus
Horses: Equine infectious anemia virus
Sheep/Goats: Small ruminant lentivirus (P-V17, formerly split into Maedi-visna virus [ovine progressive pneumonia] in sheep and caprine arthritis-encephalitis virus in goats)

References:

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.
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.
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.
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.
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; 2012:19, 21, 28, 31 56-7, 62-70.