CCR5 inhibition prevents cardiac dysfunction in the SIV/macaque model of HIV.
BACKGROUND
Diastolic dysfunction is a highly prevalent cardiac abnormality in asymptomatic as well as ART-treated human immunodeficiency virus (HIV) patients. Although the mechanisms underlying depressed cardiac function remain obscure, diastolic dysfunction in SIV-infected rhesus macaques is highly correlated with myocardial viral load. As cardiomyocytes are not productively infected, damage may be an indirect process attributable to a combination of pro-inflammatory mediators and viral proteins.


RESULTS
Given the diverse roles of CCR5 in mediating recruitment of leukocytes to inflammatory sites and serving as a receptor for HIV entry into cells, we investigated the role of CCR5 in the SIV/macaque model of diastolic dysfunction. We found that in SIV-infected macaques, CCR5 inhibition dramatically impacted myocardial viral load measured by qRT-PCR and prevented diastolic dysfunction measured by echocardiography. Complementary in vitro experiments using fluorescence microscopy showed that CCR5 ligands impaired contractile function of isolated cardiomyocytes, thus identifying CCR5 signaling as a novel mediator of impaired cardiac mechanical function.


CONCLUSIONS
Together, these findings incriminate SIV/HIV gp120-CCR5 as well as chemokine-CCR5 interactions in HIV-associated cardiac dysfunction. These findings also have important implications for the treatment of HIV-infected individuals: in addition to antiviral properties and reduced chemokine-mediated recruitment and activation of inflammatory cells, CCR5 inhibition may provide a cardioprotective benefit by preventing cardiomyocyte CCR5 signaling.
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD.
Kathleen M
KM
Kelly
Carlo G
CG
Tocchetti
Alexey
A
Lyashkov
Patrick M
PM
Tarwater
Djahida
D
Bedja
David R
DR
Graham
Sarah E
SE
Beck
Kelly A
KA
Metcalf Pate
Suzanne E
SE
Queen
Robert J
RJ
Adams
Nazareno
N
Paolocci
Joseph L
JL
Mankowski
D000818:Animals; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000494:pharmacology*; D003971:Diastole / Q000187:drug effects; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D008024:Ligands; D008253:Macaca mulatta; D000077592:Maraviroc; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D019713:Receptors, CCR5 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D014230:Triazoles / Q000494:pharmacology*; D018754:Ventricular Dysfunction / Q000175:diagnosis / Q000503:physiopathology / Q000517:prevention & control* / Q000821:virology; D016276:Ventricular Function / Q000187:drug effects*; D019562:Viral Load
D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D008024:Ligands; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc
HIV; animal model; chemokine; diastolic function; echocardiography