HIV-1 induces cardiomyopathy by cardiomyocyte invasion and gp120, tat, and cytokine apoptotic signaling
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We examined heart tissues of AIDS patients with or without HIV cardiomyopathy (HIVCM) by immunohistocheistry, in situ polymerase chain reaction, in situ riboprobe hybridization, and the TUNEL technique for apoptosis. In HIVCM tissues, only inflammatory cells, but not endothelial cells or cardiomyocytes, displayed HIV-1 DNA and RNA. However, macrophages, lymphocytes, and—in a patchy fashion—cardiomyocytes and endothelial cells exhibited virus envelope protein gp 120. Macrophages infiltrated the myocardium in a perivascular fashion and expressed tumor necrosis factor family ligands; adjacent cardiomyocytes suffered apopotosis. in vitro HIV-1 strongly invaded neonatal rat ventricular myocytes (NRVMs) and coronary artery endothelial cells (CAECs) and induced microvilli but did not replicate. HIV-1, gp120, or Tat induced Erk 1/2 phosphorylation, activation of caspase-3, and apoptosis of NRVMs and CAECs; all of these were inhibited by a MAPK/ERK-kinase (MEK) inhibitor U0126. The pathogenesis of HIVCM involves HIV-1 replication in inflammatory cells and induction of cardiomyocyte apoptosis by (1) the extrinsic pathway through apoptotic ligands and (2) the intrinsic pathway through direct virus entry and gp120-and Tat-proapoptotic signaling.
Key WordsHIV cardiomyopathy cardiomyocyte apoptosis HIV-1 envelope protein gp120 HIV-1 protein Tat macrophage
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- 1.Liu, N.Q., Lossinsky, A.S., Popik, W., Li, X., Gujuluva, C., Kriederman, B., et al. (2002). Human immunodeficiency virus type 1 enters brain microvascular endothelia by macropinocytosis dependent on lipid rafts and the mitogen-activated protein kinase signaling pathway. J. Virol. 76: 6689–6700.PubMedCrossRefGoogle Scholar
- 5.Lipshultz, S.E., Fox, C.H., Perez-Atayde, A.R., Sanders, S.P., Colan, S.D., McIntosh, K., et al. (1990). Identification of human immunodeficiency virus-1 RNA and DNA in the heart of a child with cardiovascular abnormalities and congenital acquired immune deficiency syndrome. Am. J. Cardiol. 66:246–250.PubMedCrossRefGoogle Scholar
- 6.Rodriguez, E.R., Nasim, S., Hsia, J., Sandin, R.L., Ferreira, A., Hilliard, B.A., et al. (1991). Cardiac myocytes and dendritic cells harbor human immunodeficiency virus in infected patients with and without cardiac dysfunction: detection by multiplex, nested, polymerase chain reaction in individually microdissted cells from right ventricular endomyocardial biopsy tissue. Am. J. Cardiol. 68:1511–1520.PubMedCrossRefGoogle Scholar
- 15.Deng, L., Ammosova, T., Pumfery, A., Kashanchi F., and Nekhai, S. (2002). HIV-1 tat interaction with RNA polymerase II C-terminal domain (CTD) and a dynamic association with CDK2 induce CTD phosphorylation and transcription from HIV-1 promoter. J. Biol. Chem. 277:33922–33929.PubMedCrossRefGoogle Scholar
- 20.Nuovo, G. (1997). PCR in Situ Hybridization: Protocols and Amplifications, 3rd ed. New York, NY: Lippincott-Raven.Google Scholar
- 22.October 2002. Available at:http://www.pnas.org.Accessed February 27, 2004.Google Scholar
- 25.Zhang, L., Looney, D., Taub, D., Chang, S.L., Way, D., Witte, et al. (1998). Cocaine opens the blood-brain barrier to HIV-1 invasion. J. Neuro. Virol. 4:619–626.Google Scholar