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Chemokine Receptor 5 Inhibition Prevents SIV-associated Cardiac Dysfunction

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.

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Chemokine Receptor 5 Inhibition Prevents SIV-associated Cardiac Dysfunction

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  1. 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

  2. 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

  3. 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

  4. 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

  5. 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.

  6. SIV-associated Diastolic Dysfunction

  7. Diastolic Dysfunction Correlated with SIV Replication

  8. 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

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

  10. Actin CCR5 Merge

  11. In vitro assessment of cardiomyocyte CCR5 expression

  12. CCL5 decreases contractility without altering Ca2+ flux

  13. 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

  14. CCR5Inhibition Modulates Viral Load

  15. CCR5Inhibition Preserves Diastolic Function

  16. 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

  17. 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 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)

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