Abstract
BackgroundAlthough highly active antiretroviral therapy (HAART) has dramatically reduced the morbidity and mortality associated with HIV infection, a number of antiretroviral toxicities have been described, including myocardial toxicity resulting from the use of nucleotide and nucleoside reverse transcriptase inhibitors (NRTIs). Current treatment guidelines recommend the use of HAART regimens containing two NRTIs for initial therapy of HIV-1 positive individuals; however, potential cardiotoxicity resulting from treatment with multiple NRTIs has not been addressed.Methodology/Principal FindingsWe examined myocardial tissue from twelve CD8 lymphocyte-depleted adult rhesus macaques, including eight animals infected with simian immunodeficiency virus, four of which received combined antiretroviral therapy (CART) consisting of two NRTIs [(9-R-2-Phosphonomethoxypropyl Adenine) (PMPA) and (+/−)-beta-2′,3′-dideoxy-5-fluoro-3′-thiacytidine (RCV)] for 28 days. Multifocal infiltrates of mononuclear inflammatory cells were present in the myocardium of all macaques that received CART, but not untreated SIV-positive animals or SIV-negative controls. Macrophages were the predominant inflammatory cells within lesions, as shown by immunoreactivity for the macrophage markers Iba1 and CD68. Heart specimens from monkeys that received CART had significantly lower virus burdens than untreated animals (p<0.05), but significantly greater quantities of TNF-α mRNA than either SIV-positive untreated animals or uninfected controls (p<0.05). Interferon-γ (IFN-γ), IL-1β and CXCL11 mRNA were upregulated in heart tissue from SIV-positive monkeys, independent of antiretroviral treatment, but CXCL9 mRNA was only upregulated in heart tissue from macaques that received CART.Conclusions/SignificanceThese results suggest that short-term treatment with multiple NRTIs may be associated with myocarditis, and demonstrate that the CD8-depleted SIV-positive rhesus monkey is a useful model for studying the cardiotoxic effects of combined antiretroviral therapy in the setting of immunodeficiency virus infection.
Highlights
Human immunodeficiency virus (HIV) infection has been associated with a variety of diseases of the cardiovascular system, including myocarditis [1,2,3], atherosclerosis and coronary heart disease [4,5,6,7,8,9,10,11], and cardiomyopathy and ventricular dysfunction [12]
The independent and combined contributions of HIV infection and antiretroviral therapy on myocardial disease remain unclear; a reliable animal model would benefit efforts to distinguish the impact of viral pathogenesis from antiretroviral toxicity
We investigated the pathogenesis of myocarditis in four of four CD8+ cell-depleted, simian immunodeficiency virus (SIV)-infected rhesus macaques that had been treated for 28 days with PMPA and RCV
Summary
Human immunodeficiency virus (HIV) infection has been associated with a variety of diseases of the cardiovascular system, including myocarditis [1,2,3], atherosclerosis and coronary heart disease [4,5,6,7,8,9,10,11], and cardiomyopathy and ventricular dysfunction [12]. Antiretroviral therapy has been associated with an increased risk of cardiovascular disease in HIV positive patients [7,25,26], this remains controversial [8,10,27]. Myocardial toxicity resulting from treatment with NRTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) has been reported previously; suspected mechanisms include mitochondrial toxicity and the formation of reactive oxygen species (ROS) within cardiac myocytes [28,29] [29,30,31,32,33]. Highly active antiretroviral therapy (HAART) has dramatically reduced the morbidity and mortality associated with HIV infection, a number of antiretroviral toxicities have been described, including myocardial toxicity resulting from the use of nucleotide and nucleoside reverse transcriptase inhibitors (NRTIs). Current treatment guidelines recommend the use of HAART regimens containing two NRTIs for initial therapy of HIV-1 positive individuals; potential cardiotoxicity resulting from treatment with multiple NRTIs has not been addressed
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