HIV-1 induces cardiomyopathyby cardiomyocyte invasion and gp120, Tat, and cytokine apoptotic signaling.
We examined heart tissues of AIDS patients with or without HIV cardiomyopathy (HIVCM) by immunohistochemistry, 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 gp120. Macrophages infiltrated the myocardium in a perivascular fashion and expressed tumor necrosis factor family ligands; adjacent cardiomyocytes suffered apoptosis. 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.
Fiala
Milan
M
Department of Medicine, Greater Los Angeles VA Medical Center, Los Angeles, CA 90095-1760, USA. fiala@ucla.edu
Popik
Waldemar
W
Qiao
Jian-Hua
JH
Lossinsky
Albert S
AS
Alce
Timothy
T
Tran
Kenix
K
Yang
Wendy
W
Roos
Kenneth P
KP
Arthos
James
J
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016207:Cytokines / Q000502:physiology*; D004279:DNA, Viral / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015696:Gene Products, tat / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D015658:HIV Infections / Q000150:complications*; D015497:HIV-1; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000821:virology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D054322:tat Gene Products, Human Immunodeficiency Virus
D016207:Cytokines; D004279:DNA, Viral; D015696:Gene Products, tat; D015699:HIV Envelope Protein gp120; D012367:RNA, Viral; D054322:tat Gene Products, Human Immunodeficiency Virus; D048049:Extracellular Signal-Regulated MAP Kinases; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases