Chemokine Receptor 5 Inhibition Prevents SIV-associated Cardiac

DysfunctionKatie Kelly Brennan, DVM

Johns Hopkins University School of Medicine Department of Molecular and Comparative Pathobiology

Objectives

• Discuss HIV-associated cardiac dysfunction and describe our simian immunodeficiency virus (SIV)/macaque model

• Describe role of chemokine co-receptor CCR5 in virus-associated cardiac dysfunction– In vitro- assess cardiomyocytes for functional CCR5 – In vivo- CCR5 inhibition in SIV-macaque model

HIV-associated cardiac dysfunction

• Overt clinical cardiac manifestations: 5 to 23%• Association of myocarditis with function decline

undefined• LV systolic and diastolic dysfunction

• 60% of asymptomatic HIV+ • HAART

Diastolic dysfunction

• Functional abnormalities that exist during left ventricular relaxation and filling– Normal left ventricular volume and

ejection fraction– Increased left ventricular pressure

• Risk for development of heart failure and reduced survival

SIV-A Model of HIV Cardiomyopathy

• Myocarditis observed in SIV-infected macaques• LV systolic dysfunction: ventricular dilation and

decreased ejection fraction • Tool for understanding relationship between

functional decline and host immune responses and/or viral replication

Hypothesis: SIV infected macaques also develop diastolic dysfunction.

SIV-associated Diastolic Dysfunction

Diastolic Dysfunction Correlated with SIV Replication

SIV/Macaque Model: Clinical Conclusions

Diastolic dysfunction develops in SIV-infected macaques

Differences in myocardial lesions and SIV infection status not correlated to diastolic dysfunction

Diastolic dysfunction not correlated to macrophage activation

SIV RNA in heart strongly correlated with prolonged IVRT

SIV is a model for HIV-associated diastolic dysfunction

CCR5

• 7 CC chemokine, 7-transmembrane GPCR receptor • Expressed on T cells and macrophages, important to

the regulation of leukocyte trafficking/activation• Acting with CD4, major co-receptor for HIV and SIV

– Mediates CD4 independent viral infection

Hypothesis: Activation of cardiomyocyte CCR5 chemokine coreceptor triggered by binding of HIV/SIV envelope glycoprotein or cognate chemokine mediates cardiac dysfunction.

www.cdc.gov/ncidod/eid/vol3no3/smith.htm

Actin CCR5

Merge

In vitro assessment of cardiomyocyte CCR5 expression

CCL5 decreases contractility without altering Ca2+ flux

Diastolic Function during Maraviroc Monotherapy in SIV-infected Macaques

• 6 dual innoculated rhesus macaques

• Maraviroc montherapy (200mg PO q12) initiated @ d24

• Viral load, leukocyte parameters, drug concentration & cardiac function measured over time

• Euthanized @ d180

CCR5 Inhibition Modulates Viral Load

CCR5 Inhibition Preserves Diastolic Function

Conclusions

• SIV/macaque model is relevant to HIV-associated cardiac disease

• Addition of CCL5 to isolated cardiomyocytes decreased contractility which was reversed by Maraviroc– CCR5 expression on cardiomyocytes may mediate cardiac

dysfunction function in vivo

• Maraviroc monotherapy is cardioprotective in the SIV macaque model

Thanks!

Retrovirus lab• Joe Mankowski • Chris Zink• Janice Clements • David Graham• Suzanne Queen• Kelly Pate• Sarah Beck• Brandon Bullock• Ming Li• Chris Bartizal• Alexey Lyashkov• Lucio Gama• Jami Karper• Jamie Dorsey• Veronica Aquino

Molecular and Comparative Pathobiology• Bob Adams• Bruce Baldwin• Djahida Bedja• Kathy GabrielsonDepartment of Medicine, Cardiology• Gab Tocchetti• Naz Paolocci• Dave Kass• Rick TuninJohn Gibas, GastroenterologyPathobiology Graduate ProgramACVP-STP Coalition

Mark Cartwright, Merck

NIH RR 07002, R01 HL078479 (JLM)