title: Anti-α4 Integrin Antibody Blocks Monocyte/Macrophage Traffic to the Heart and Decreases Cardiac Pathology in a SIV Infection Model of AIDS.
abstract: BACKGROUND
  Cardiovascular disease (CVD), myocarditis and fibrosis are comorbidities of HIV(+) individuals on durable antiretroviral therapy (ART). Although mechanisms for these vary, monocytes/macrophages are increasingly demonstrated to be key players.
  
  
  RESULTS
  We directly blocked monocyte/macrophage traffic to the heart in an SIV model of AIDS using an anti-alpha-4 integrin antibody (natalizumab). Nineteen Rhesus macaques were SIVmac251 infected and CD8-lymphocyte depleted for the development of rapid AIDS. Ten animals received natalizumab once a week, for 3 weeks, and were sacrificed 1 week later. Six animals began treatment at the time of infection (early) and the remaining 4 began treatment 28 days post-infection (late), a time point we have previously established when significant cardiac inflammation occurs. Nine animals were untreated controls; of these, 3 were sacrificed early and 6 were sacrificed late. At necropsy, we found decreased SIV-associated cardiac pathology in late natalizumab-treated animals, compared to untreated controls. Early and late treatment resulted in significant reductions in numbers of CD163(+) and CD68(+) macrophages in cardiac tissues, compared to untreated controls, and a trend in decreasing numbers of newly recruited MAC387(+) and BrdU(+) (recruited) monocytes/macrophages. In late treated animals, decreased macrophage numbers in cardiac tissues correlated with decreased fibrosis. Early and late treatment resulted in decreased cardiomyocyte damage.
  
  
  CONCLUSIONS
  These data demonstrate a role for macrophages in the development of cardiac inflammation and fibrosis, and suggest that blocking monocyte/macrophage traffic to the heart can alleviate HIV- and SIV-associated myocarditis and fibrosis. They underscore the importance of targeting macrophage activation and traffic as an adjunctive therapy in HIV infection.
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA (J.A.W., G.A.B., J.H.C., T.H.B., K.C.W.).
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Walker
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA (J.A.W., G.A.B., J.H.C., T.H.B., K.C.W.).
authors.forename: Graham A
authors.initials: GA
authors.lastname: Beck
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA (J.A.W., G.A.B., J.H.C., T.H.B., K.C.W.).
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Campbell
authors.affiliation: Section of Anatomic Pathology, Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (A.D.M.).
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Miller
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA (J.A.W., G.A.B., J.H.C., T.H.B., K.C.W.).
authors.forename: Tricia H
authors.initials: TH
authors.lastname: Burdo
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA (J.A.W., G.A.B., J.H.C., T.H.B., K.C.W.).
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Williams
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D009202:Cardiomyopathies / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D002633:Chemotaxis / Q000187:drug effects*; D019610:Cytoprotection; D004195:Disease Models, Animal; D005355:Fibrosis; D016867:Immunocompromised Host; D007155:Immunologic Factors / Q000494:pharmacology*; D039441:Integrin alpha4 / Q000276:immunology* / Q000378:metabolism; D008253:Macaca mulatta; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D009205:Myocarditis / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000069442:Natalizumab / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000472:pathogenicity; D013997:Time Factors; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D007155:Immunologic Factors; D000069442:Natalizumab; D011956:Receptors, Cell Surface; D039441:Integrin alpha4
keywords: HIV; animal model; cardiomyopathy; fibrosis; myocarditis