Chemokine Receptor 5 Inhibition Prevents SIV-associated Cardiac Dysfunction - PowerPoint Presentation

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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

Discuss HIV-associated cardiac dysfunction and describe our simian immunodeficiency virus (SIV)/macaque modelDescribe 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 undefinedLV systolic and diastolic dysfunction60% of asymptomatic HIV+ HAART

Diastolic dysfunction

Functional abnormalities that exist during left ventricular relaxation and fillingNormal left ventricular volume and ejection fractionIncreased 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/activationActing with CD4, major co-receptor for HIV and SIVMediates CD4 independent viral infectionHypothesis: 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 Ca

2+

flux

Diastolic Function during Maraviroc

Monotherapy in SIV-infected Macaques6 dual

innoculated rhesus macaquesMaraviroc montherapy (200mg PO q12) initiated @ d24Viral 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 diseaseAddition of CCL5 to isolated cardiomyocytes decreased contractility which was reversed by Maraviroc

CCR5 expression on cardiomyocytes may mediate cardiac dysfunction function in vivoMaraviroc monotherapy is cardioprotective in the SIV macaque model

Thanks!

Retrovirus labJoe Mankowski

Chris ZinkJanice Clements David GrahamSuzanne QueenKelly PateSarah BeckBrandon BullockMing Li

Chris BartizalAlexey Lyashkov

Lucio Gama

Jami Karper

Jamie Dorsey

Veronica Aquino

Molecular and Comparative

Pathobiology

Bob Adams

Bruce Baldwin

Djahida Bedja

Kathy Gabrielson

Department of Medicine, Cardiology

Gab Tocchetti

Naz

Paolocci

Dave

Kass

Rick

Tunin

John Gibas, Gastroenterology

Pathobiology

Graduate Program

ACVP-STP Coalition

Mark Cartwright, Merck

NIH RR 07002, R01 HL078479 (JLM)