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

Abstract

Human immunodeficiency virus (HIV) comorbidities have become clinically more important due to antiretroviral therapy. Although therapy increases life expectancy, it does not completely suppress immune activation and its associated complications. The simian immunodeficiency virus (SIV)-infected rhesus macaque (Macaca mulatta) represents a valuable model for the investigation of SIV-associated diseases. Although cardiovascular (CV) changes are common in HIV-infected patients, there are only a few reports on the incidence of CV findings in SIV-infected animals. In addition, potential associations between pathohistological findings and hematological parameters are still unclear. We therefore conducted a retrospective analysis of 195 SIV-infected rhesus macaques that were euthanized with AIDS-related symptoms at the German Primate Center, Goettingen, over a 25-year period. Pathological findings were correlated with hematological data. The main findings included myocarditis (12.8 %), endocarditis (9.7 %), and arteriopathy (10.3 %) in various organs. Thrombocytopenia occurred more frequently in macaques with endocarditis or arteriopathy than in macaques without CV disease (80 % in animals with endocarditis, 60 % in animals with arteriopathy, $p<0.0001$ and $p=0.0016$ , respectively). Further investigations of the interaction between coagulation markers, proinflammatory cytokines, and biomarkers associated with endothelial dysfunction (e.g., D-dimers) and histological data (vascular wall structure) may unravel the mechanisms underlying HIV/SIV-associated CV comorbidities.

Figure 1

Occurrence and combination of classical major cardiovascular (CV) findings in SIV-infected rhesus macaques (Macaca mulatta) ($n=\mathrm{195}$).

Figure 2

Cardiovascular findings in SIV-infected rhesus macaques (Macaca mulatta). (a) Rhesus monkey, no. G5550, infected with SIVmac251, heart. Severe myocarditis with infiltration of lymphohistiocytic cells between muscle fibers. HE stain. Scale bar $=$ 100 $\mathrm{\mu }$m. (b) Rhesus monkey, no. G5550, infected with SIVmac251, heart. Infiltrating histiocytic cells express SIV antigen. Immunohistochemistry with KK75. Scale bar $=$ 100 $\mathrm{\mu }$m. (c) Rhesus monkey, no. G9095, infected with SIVmac251, heart. Verrucous masses on the mitral valve occluding the lumen. (d) Rhesus monkey, no. G9095, infected with SIVmac251, heart. The verrucous mass consists of platelets, fibrin, and bacterial colonies. There are fibrotic changes of the myocardium with mild inflammatory cell infiltration. HE stain. Scale bar $=$ 0.5 mm. (e) Rhesus monkey, no. K780, infected with SIVmac251/32H. Medium-sized artery with thickened vessel wall. HE stain. Scale bar $=$ 100 $\mathrm{\mu }$m. (f) Rhesus monkey, no. G7685, infected with SIVmac239, lung. Medium-sized artery with thickened vessel wall and occluded lumen with multifocal recanalization. HE stain. Scale bar $=$ 100 $\mathrm{\mu }$m.

Figure 3

Correlation of pre-infection CD4 $/$ CD8 ratios with survival time. CD4${}^{+}$ and CD8${}^{+}$ lymphocyte populations were determined by flow cytometric analysis as percentages of CD3${}^{+}$ cells. Their ratios correlate with survival time after SIV infection ($n=\mathrm{115}$, $p<\mathrm{0.0001}$, rs $=$ 0.39, Spearman rank correlation). Each pre-infection value corresponds to the mean of two to three independent measurements.