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. METHODS AND 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.