Background:  Cardiovascular disease (CVD) is an emerging complication in HIV⁺ patients receiving HAART. Although HAART is known to be associated with metabolic syndrome, a cluster of CVD risk factors, the mechanism of HAART toxicity is unknown.

Methods:  This retrospective study used tissues from 8 CD8⁺ cell-depleted adult rhesus macaques infected with simian immunodeficiency virus (SIV)_mac251. We treated 4 of the animals for 28 days with racivir (RCV) and tenofovir (TDF), beginning 28 days post-inoculation; 4 CD8⁺ cell-depleted, uninfected animals served as additional controls. Histopathologic examination for inflammatory and degenerative lesions was performed on hematoxylin and eosin-stained sections of cardiac tissue. Viral replication in cardiac sections was evaluated by in situ hybridization for SIV RNA. The level of inflammation was assessed by immunohistochemistry, using antibodies to identify macrophages (Iba1), B lymphocytes (CD20), T lymphocytes (CD8), interleukin (IL) -18, and caspase-3. The extent of myocardial fibrosis was evaluated by staining tissues for collagen deposition (Masson’s trichrome stain).

Results:  Multifocal mononuclear cell infiltrates were present in the heart tissue of animals that received ART. No inflammatory lesions were present in untreated SIV⁺ controls. However, occasional small mononuclear infiltrates were seen in 2 of 4 uninfected controls. Degenerative changes in cardiomyocytes included loss of cross-striations, hyalinization, and swelling. Rare atrophic and necrotic cardiomyocytes were seen only in tissue sections of treated animals. Myocardial fibrosis was not observed in any group. The inflammatory cells were positive for the macrophage marker Iba1 and negative for CD8 and CD20, suggesting the absence of lymphocytes in inflammatory foci. Expression of IL-18 was not observed in either treated or untreated controls, suggesting that the inflammation is not directly mediated by IL-18. In addition, caspase-3 expression was not seen in degenerating cardiomyocytes, indicating that the caspase-3 apoptotic pathway is not involved.

Conclusions:  Macrophages are the predominant inflammatory cells involved in short-term ART-associated myocarditis; however, the mechanisms mediating inflammation are unknown. This pilot assessment suggests that the process is IL-18 and caspase-3 independent. Further studies are needed to elucidate the mechanism of myocardial damage.