CCR5 inhibition prevents cardiac dysfunction in the SIV/macaque model of HIV.

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. 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. 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.