Five-year-old male rhesus macaque (Macaca mulatta).This animal was assigned to the research project of alcohol, HIV infection & host defense. Ethanol was administered via the gastric catheter with 30% ethanol in water (w/v) as a 0.5-hour prime, followed immediately by a 4.5-hour maintenance infusion. The concentration of ethanol in blood was 50 to 60 mM. The animals received ethanol four consecutive days per week for the duration of the study. Three months after ethanol administration, this animal was intravenously inoculated with simian immunodeficiency virus (SIV) 251 about one year before sacrifice. Streptococcus pneumoniae was inoculated in right lung seven months before sacrifice.

Six months after SIV inoculation, this animal began to show chronic, mild leukocytosis, mild neutrophilia, and moderate thrombocytopenia. The animal developed weight loss, loss of muscle mass, enlargement and restriction of stifles, enlarged lymphoid tissue, and mild splenomegaly and hepatomegaly.

Gross Description:  

Presented was a severely thin animal with no body fat. A catheter tube was inserted on the left dorsal-lateral back, tunneled through subcutaneous, and ended at the left side of stomach. The spleen was markedly enlarged with prominent white pulp. All peripheral lymph nodes were four to six times enlarged. This animal had mild to moderate thymic and muscular atrophy.

Histopathologic Description:

Kidney: Multifocally the small and medium-sized arteries are expanded and variably disrupted by proliferation of the tunica intima, smooth muscular hyperplasia, and infiltration of inflammatory cells. The lumina of affected arteries are partially to completely occluded and lined by hypertrophic endothelial cells. Usually, the tunica media are segmentally to circumferentially thickened by smooth muscle hyperplasia, fragmented collagen bundles, and reactive fibroblasts. The tunica adventitia is markedly expanded by numerous neutrophils, lymphocytes, plasma cells, and fewer macrophages and eosinophils. Some subendothelial tunica intima and tunica media are disrupted and markedly expanded by thick bands of deeply eosinophilic hyaline to fibrinoid material admixed with cellular and karyorrhectic debris and many erythrocytes (necrosis and hemorrhage). Multifocally the renal tubules are ectatic, lined by attenuated epithelial cells, and contain hypereosinophilic homogenous material (protein casts) and cellular debris. Multifocally the interstitium is infiltrated by many lymphocytes and plasma cells. Occasionally the interstitium is expanded by lymphoid aggregates (lymphoid hyperplasia and dysplasia). Some glomerular tufts are senescent and shrunken with ectatic Bowman’s spaces.

Morphologic Diagnosis:  

1. Kidney, medium and small arteries: Arteritis, proliferative and necrotizing, multifocal.
2. Kidney, lymphoplasmacytic interstitial nephritis, multifocal, mild.
3. Kidney, interstitial lymphoid hyperplasia and dysplasia.

Lab Results:  



Polyarteritis nodosa-like syndrome/SIV

Contributor Comment:  

Arteriopathy is also noted in the small to medium arteries of the mesentery, testis, liver, gall bladder, pancreas, urinary bladder, and bone marrow. The systemic vascular lesions in this monkey resemble those found in polyarteritis nodosa (PAN)-like syndrome in HIV patients. PAN-like syndrome has been described in HIV patients in the literature.6,7 While target organs are usually muscles, nerves, skin and gastrointestinal tract, renal polyarteritis nodosa in HIV patients has also been reported.2 PAN-like syndrome occurs in fewer than 1% of HIV patients. The underlying mechanism is thought to involve cell or immune-complex-mediated inflammation, like classic PAN in other species. Although the histopathological changes are similar between two entities, there are several important differences between PAN in HIV patients and so-called classic or idiopathic PAN. First, the waxing and waning clinical course of classic PAN is not seen in patients with HIV infection. Second, classic PAN can be associated with hepatitis B virus infections, but in HIV patients, the serology for HBV is always negative. Third, the affected arteries in HIVassociated PAN tend to be smaller than that seen in classic PAN.4 PAN-like syndrome has been reported in two SIV-infected rhesus macaques.11 Vasculopathy is prominent in kidney, intestine, pancreas, liver, heart, lymph nodes, spleen, and testis. Histologically, disseminated arteriopathy is characterized by intimal thickening and fibrosis with varying degrees of vasculitis. Intranuclear inclusion bodies were CMV positive by immunohistochemistry in multiple organs in these two monkeys. Intranuclear inclusion bodies were not observed in the current case but immunohistochemistry for CMV or other viral agents was not performed in the current case. Pulmonary arteriopathy is the most common vasculopathy in macaques infected with SIV. Nineteen of 85 animals infected with SIV developed pulmonary arteriopathy characterized by intimal thickening, luminal occlusion, and internal elastic laminae fragmentation and interruption.3 Pulmonary artery hyperplasia and/or plexiform arteriopathy were present in eight of 13 (62%) SHIV-infected macaques.5 However, the pulmonary arteries were histopathologically normal in the current case. This observation is consistent with the two published cases, in which, arteriopathy was mild or absent in the lungs.11 These observations suggested a different pathogenesis between pulmonary arteriopathy and PANlike syndrome in SIV infected monkeys.

Based on extensive experience on this model, it is unlikely that ethanol administration was associated with PAN-like syndrome in this monkey. There is no documentation of alcohol and arteriopathy in the literature. Although this animal was inoculated with Streptococcus pnenumonae, grossly and microscopically there was no current evidence of Streptococcus infection. Renal interstitial lymphoid hyperplasia and dysplasia are not uncommon findings in SIV-infected monkeys.

JPC Diagnosis:  

1. Kidney, small arteries and arterioles: Arteriopathy, proliferative and necrotizing, multifocal, mild to marked, with adventitial inflammation, rhesus macaque (Macaca mulatta).
2. Kidney: Interstitial nephritis, lymphoplasmacytic, multifocal, mild.

Conference Comment:  

Although the specific etiology and pathogenesis of this lesion are unclear, the contributor provides an excellent example of a polyarteritis nodosa (PAN)-like syndrome in a nonhuman primate. PAN-like syndromes are thought to be a type III hypersensitivity reaction secondary to antigen:antibody complex deposition in medium to small caliber arteries.1 Immune complex deposition results in complement activation leading to segmental, circumferential, and proliferative arteritis. This syndrome has been well described in the aged SpragueDawley rat and beagles.9,10 In rats, lesions most often occur in the muscular mediumsized arteries of the mesentery, pancreas, testis, hepatic, coronary, uterine, cerebral, adrenal, and renal arteries. 10 This condition in beagles is associated with beagle pain syndrome. In these cases, the coronary and meningeal arteries are most affected, and clinically dogs are febrile, lose weight, and have cervical pain.9 Typically in domestic species, PAN-like syndrome spares the pulmonary circulation, large arteries and glomeruli. 11 The association of SIV as part of the pathogenesis of the arteriole lesions, in this case, remains unclear.

The JPC strives to avoid using the suffix “- opathy” in a morphologic diagnosis due to its non-specific nature; however, in rare instances, this terminology may be appropriate, especially in cases where the primary process underlying the lesion is difficult to ascertain. While the SIV-positive status of this particular animal suggests a causal relationship, PAN has also been seen as a spontaneous finding in macaques, as well as a toxic lesion association with administration of cyclosporine and tacrolimus (WSC 2003-2004, Conference 20, Case 1). The term arteriopathy can be modified by other descriptors such as proliferative and necrotizing to further define the underlying process. Much of the literature on this disease uses the term arteriopathy to describe this finding in arteries and arterioles in SIV-infected rhesus macaques.

During a discussion of the vessel wall changes in this case, some conference participants preferred the term hyaline change to describe the circumferential homogenous, eosinophilic, proteinaceous material deposited within the external elastic membrane of arterioles rather than the wellensconced term fibrinoid necrosis. Fibrinoid necrosis has been classically used by both human and veterinary pathologists to describe the brightly eosinophilic changes in the injured vessel associated with immune complex, plasma protein, and complement protein deposition within vessels.1 Fibrinoid necrosis implies a pathogenesis that may or may not be present. The brightly eosinophilic homogenous protein accumulation obscures the structural detail of the blood vessel, thus making it difficult or impossible to determine if there is fibrin or necrosis present within the arteriole wall. Hyalinosis describes the accumulation of leaked eosinophilic proteinaceous material secondary to endothelial damage and increased vascular permeability without making assumptions about the pathogenesis.

Finally, several participants found multinucleated giant cells within the tubular epithelium and lumina of collecting ducts within their sections. Multinucleated giant cells have been described as a common incidental finding in macaques8 ; however, a number of participants ascribed them as a potential corroborating sign of lentivirus infection in this macaque.


1. Alpers C, Chang A. The kidney. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia, PA:Saunders Elsevier; 2015:903.

2. Angulo JC, Lopez JI, Garcia ME, Peiro J, Flores N: HIV infection presenting as renal polyarteritis nodosa. Int Urol Nephrol. 1994; 26(6):637-641.

3. Chalifoux LV, Simon MA, Pauley DR, MacKey JJ, Wyand MS, Ringler DJ: Arteriopathy in macaques infected with simian immunodeficiency virus. Lab Invest. 1992:67(3):338-349.

4. Chetty R: Vasculitides associated with HIV infection. J Clin Pathol. 2001; 54(4):275-278.

5. George MP, Brower A, Kling H, Shipley T, Kristoff J, Reinhart TA, et al.: Pulmonary vascular lesions are common in SIV- and SHIV-envinfected macaques. AIDS Res Hum Retroviruses. 2011; 27(2):103-111.

6. Gisselbrecht M, Cohen P, Lortholary O, Jarrousse B, Gayraud M, Lecompte I, et al.: Human immunodeficiency virus-related vasculitis. Clinical presentation of and therapeutic approach to eight cases. Ann Med Interne. 1998; 149(7):398- 405.

7. Libman BS, Quismorio FP, Jr., Stimmler MM: Polyarteritis nodosalike vasculitis in human immunodeficiency virus infection. J Rheumatol. 1995; 22(2):351-355.

8. Lowentine, L.J. A primer of primate pathology lesions and nonlesions. Tox Pathol 2003; 31:91-102.

9. Miller L, Van Vleet J, Gal A. Cardiovascular system and lymphatic vessels. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis, MO:Mosby Elsevier; 2012:587.

10. Percy DH, Barthold SW. Rat. In: Pathology of Laboratory Rodents and Rabbits, 4th ed., Ames, IA: Blackwell Publishing; 2016:156.

11. Robinson W, Robinson N. Cardiovascular system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA:Elsevier; 2016:71.

12. Yanai T, Lackner AA, Sakai H, Masegi T, Simon MA: Systemic arteriopathy in SIV-infected rhesus macaques (Macaca mulatta). J Med Primatol. 2006; 35(2):106-112.

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3-4. Kidney, macaque.

3-1. Kidney, macaque.

3-2. Kidney, macaque.

3-3. Kidney, macaque.

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