Myocarditis in CD8-depleted SIV-infected rhesus macaques after short-term dual therapy with nucleoside and nucleotide reverse transcriptase inhibitors

• Published in: PloS one 2010-12, Vol.5 (12), p.e14429
• Main Authors: Annamalai, Lakshmanan, Westmoreland, Susan V, Domingues, Heber G, Walsh, Dennis G, Gonzalez, R Gilberto, O'Neil, Shawn P
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Adenine; AIDS; Animals; Antiretroviral agents; Antiretroviral Therapy, Highly Active; B cells; Base Sequence; Biological response modifiers; Cardiotoxicity; Cardiovascular disease; Cardiovascular Disorders/Heart Failure; CD8 antigen; CD8 Antigens - biosynthesis; CXCL11 protein; Depletion; DNA polymerases; Health aspects; Heart; Heart diseases; Highly active antiretroviral therapy; HIV; HIV infections; Human immunodeficiency virus; IL-1β; Immunoreactivity; Infection; Infections; Infectious Diseases/HIV Infection and AIDS; Inflammation; Inhibitors; Interferon; Lesions; Lymphocytes; Lymphocytes - virology; Macaca mulatta; Macrophages; Macrophages - virology; Molecular Sequence Data; Monkeys; Morbidity; Myocarditis; Myocarditis - virology; Myocardium; Myocardium - metabolism; Nucleoside reverse transcriptase inhibitors; Nucleosides; Nucleosides - chemistry; Nucleotides - chemistry; Reverse transcriptase inhibitors; Reverse Transcriptase Inhibitors - pharmacology; RNA; RNA-directed DNA polymerase; Simian Acquired Immunodeficiency Syndrome - drug therapy; Simian immunodeficiency virus; Simian Immunodeficiency Virus - metabolism; Therapy; Toxicity; Tumor necrosis factor-α; Virology/Animal Models of Infection; Virology/Host Antiviral Responses; Virology/Immunodeficiency Viruses; Virology/New Therapies, including Antivirals and Immunotherapy; Viruses; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0014429

Although 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. We 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