chemokine receptor 5 inhibition prevents siv-associated cardiac dysfunction
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Chemokine Receptor 5 Inhibition Prevents SIV-associated Cardiac Dysfunction. Katie Kelly Brennan, DVM Johns Hopkins University School of Medicine Department of Molecular and Comparative Pathobiology. Objectives. - PowerPoint PPT PresentationTRANSCRIPT
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Chemokine Receptor 5 Inhibition Prevents SIV-associated Cardiac
DysfunctionKatie Kelly Brennan, DVM
Johns Hopkins University School of Medicine Department of Molecular and Comparative Pathobiology
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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
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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
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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
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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.
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SIV-associated Diastolic Dysfunction
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Diastolic Dysfunction Correlated with SIV Replication
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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
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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
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Actin CCR5
Merge
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In vitro assessment of cardiomyocyte CCR5 expression
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CCL5 decreases contractility without altering Ca2+ flux
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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
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CCR5 Inhibition Modulates Viral Load
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CCR5 Inhibition Preserves Diastolic Function
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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
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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)