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Direct Targeting of Macrophages With Methylglyoxal-Bis-Guanylhydrazone Decreases SIV-Associated Cardiovascular Inflammation and Pathology

Walker, Joshua A. PhD; Miller, Andrew D. DVM, DACVP; Burdo, Tricia H. PhD; McGrath, Michael S. PhD; Williams, Kenneth C. PhD

JAIDS Journal of Acquired Immune Deficiency Syndromes: 15 April 2017 - Volume 74 - Issue 5 - p 583–592
doi: 10.1097/QAI.0000000000001297
Basic Science

Background: Despite effective combination antiretroviral therapy, HIV-infected individuals develop comorbidities, including cardiovascular disease, where activated macrophages play a key role. To date, few therapies target activated monocytes and macrophages.

Methods: We evaluated a novel oral form of the polyamine biosynthesis inhibitor methylglyoxal-bis-guanylhydrazone (MGBG) on cardiovascular inflammation, carotid artery intima–media thickness (cIMT), and fibrosis in a simian immunodeficiency virus infection model of AIDS. Eleven simian immunodeficiency virus–infected animals received MGBG (30 mg/kg) once daily and 8 received a placebo control both beginning at 21 days postinfection (dpi). Animals were time sacrificed at 49 days post infection (dpi), when their matched placebo controls developed AIDS (63, 70, 77, 80), or at the study end-point (84 dpi). Aorta, carotid artery, and cardiac tissues were analyzed. Quantitative analyses of macrophage populations and T lymphocytes were done and correlated with cIMT and fibrosis.

Results: MGBG treatment resulted in 2.19-fold (CD163+), 1.86-fold (CD68+), 2.31-fold (CD206+), and 2.12-fold (MAC387+) decreases in macrophages in carotid arteries and significant 2.07-fold (CD163+), 1.61-fold (CD68+), 1.95-fold (MAC387+), and 1.62-fold (CD206+) decreases in macrophages in cardiac tissues. cIMT (1.49-fold) and fibrosis (2.05-fold) also were significantly decreased with MGBG treatment. Numbers of macrophage and the degree of fibrosis in treated animals were similar to uninfected animals. A positive correlation between decreased macrophage in the carotid artery and cIMT, and cardiac macrophages and fibrosis was found.

Conclusions: These data demonstrate that directly targeting macrophages with MGBG can reduce cardiovascular inflammation, cIMT, and fibrosis. They suggest that therapies targeting macrophages with HIV could be used in conjunction with combination antiretroviral therapy.

*Department of Biology, Boston College, Chestnut Hill, MA;

Cornell University College of Veterinary Medicine, Ithaca, NY; and

Department of Pathology and Laboratory Medicine, UCSF, San Francisco, CA.

Correspondence to: Kenneth C. Williams, PhD, Department of Biology, Boston College, 140 Commonwealth Avenue Higgins Hall 468, Chestnut Hill, MA 02467 (e-mail: Kenneth.williams.3@bc.edu).

Supported by the following Grants: R01 NS040237 (K.C.W.), R01 NS082116 (T.H.B.), and U19MH08183 (M.S.M.).

Parts of these data were presented at the Conference on Retroviruses and Opportunistic Infections, February 22, 2016, Boston, MA.

M.S.M is a shareholder and consultant in Pathologica, LLC. The remaining authors have no conflicts of interest to disclose.

Received April 29, 2016

Accepted January 11, 2017

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.