Open AccessCCR 5 Inhibition Prevents Cardiac Dysfunction in the SIV /Macaque Model of HIV
Author(s) -
Kelly Kathleen M.,
Tocchetti Carlo G.,
Lyashkov Alexey,
Tarwater Patrick M.,
Bedja Djahida,
Graham David R.,
Beck Sarah E.,
Metcalf Pate Kelly A.,
Queen Suzanne E.,
Adams Robert J.,
Paolocci Nazareno,
Mankowski Joseph L.
Publication year - 2014
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.114.000874
Subject(s) - medicine , simian immunodeficiency virus , chemokine , viral load , diastole , macaque , inflammation , asymptomatic , immunology , ccr5 receptor antagonist , cardiac function curve , chemokine receptor , cardiac dysfunction , virus , virology , heart failure , biology , neuroscience , blood pressure
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. Methods and 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‐ CCR 5 as well as chemokine‐ CCR 5 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, CCR 5 inhibition may provide a cardioprotective benefit by preventing cardiomyocyte CCR 5 signaling.