SIV-Associated Myocarditis: Viral and Cellular Correlates of Inflammation Severity

Abstract

Myocarditis is a common finding in HIV-infected people. Cardiac inflammatory lesions and functional abnormalities similar to those documented in HIV infection are frequently seen in SIV infection of rhesus monkeys, suggesting a shared disease mechanism. A retrospective analysis of cardiac tissue collected at necropsy was performed to assess correlates of myocardial inflammation in SIV-infected rhesus monkeys. Intramyocardial SIV-infected cells were identified in 7 of 21 hearts from SIV-infected animals, with viral protein consistently colocalizing with the macrophage marker HAM 56. Productively infected cells occurred in low numbers, and did not correlate with the presence or quantity of inflammation or necrosis. Intramyocardial CMV was identified in 6 of 21 hearts from SIV+ animals, but also did not correlate with the presence or quantity of inflammation or necrosis. In contrast, T cell infiltration correlated inversely with DC-SIGN+ cell numbers, which occurred in significantly higher numbers in SIV+ animals with histologically normal myocardium than in SIV+ animals with active or borderline myocarditis or in uninfected controls (p < 0.001), suggesting an important immunoregulatory role for this population within the myocardium.

Elevated Numbers of CD163+ Macrophages in Hearts of Simian Immunodeficiency Virus-Infected Monkeys Correlate with Cardiac Pathology and Fibrosis

“…43 In these studies, there were increased numbers of CD163 + macrophages in SIV-infected animals with normal, uninflammed heart tissue, and fewer CD163 + macrophages in SIV-infected animals with active or borderline myocarditis.…”

“…42 Yearley et al found 1-4 SIV-infected macrophages/mm 2 in hearts of 7 of 21 animals. 43 These authors used an antibody against SIV-nef that detects latent and productively infected macrophages. We found SIV-p28 and SIV-RNA-positive macrophages in brains and lymph nodes of the animals in our study.…”

Mucosal Trafficking of Vector-Specific CD4 + T Lymphocytes following Vaccination of Rhesus Monkeys with Adenovirus Serotype 5

“…Briefly, tissue sections were heated and rehydrated, incubated in 1% hydrogen peroxide in methanol (CD4) or 3% hydrogen peroxidase in phosphate-buffered saline (PBS) (HLA-DR, Ki67, and CD3), and subjected to antigen retrieval procedures, including microwaving in 0.01 M citrate buffer (Dako, Carpinteria, CA) (Ki67 and CD3) or heating under pressure in 1 mM EDTA-0.05% Tween (CD4), as previously described (11). Nonspecific staining was blocked with Dako protein block, and sections were incubated overnight at 4°C with primary antibodies to Ki67, HLA-DR, CD3 (Dako), or CD4 (Vector Laboratories, Burlingame, CA) or appropriate isotype-matched irrelevant MAb controls, followed by incubation with biotinylated secondary antibody (Dako).…”

Revisiting a quarter of a century of simian immunodeficiency virus (SIV)-associated cardiovascular diseases at the German Primate Center

“…However, it cannot be excluded that this finding may be an indication of general lymphatic activation during the course of SIV infection (Yearley et al, 2006). The percentages of the other minor CV findings (hydropericardium, dilatative cardiomyopathy, myocardial fibrosis, and myocardial hypertrophy) were previously not defined as being SIV-specific and correspond to findings which can regularly be found in healthy rhesus macaques, regarding their extent and severity (Chamanza et al, 2006).…”

“…Altered arterial walls and cardiomyocytes were immunohistochemically negative for SIV antigen. Myocarditis seems to be unrelated to the infection of cardiomyocytes with SIV (Yearley et al, 2006), but it may be associated with the accumulation of inflammatory cells in heart tissue in the context of the general activation of the immune system and regional microbial translocation (Pandrea et al, 2015). The disparity in the extent and intensity of IHC staining with the two different antibodies is likely attributable to the fact that the antibodies are directed against different proteins.…”