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HIV and Other Lentiviral Infections Cause Defects in Neutrophil Chemotaxis, Recruitment, and Cell Structure: Immunorestorative Effects of Granulocyte-Macrophage Colony-Stimulating Factor¹

Bryan Heit^*, Gareth Jones^*, Derrice Knight^*, Joseph M. Antony, M. John Gill^*, Christopher Brown^*, Christopher Power and Paul Kubes^2,*

^* Immunology Research Group, Department of Physiology and Biophysics, Department of Clinical Neuroscience, and Department of Medicine, University of Calgary, Alberta, Canada; and Department of Medicine, and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada

Patients with HIV infection exhibit deficits in bacterial and fungal clearance, and possibly depressed innate immunity. In this study, we observed that neutrophils from HIV-infected patients have a profound defect in chemotaxis in response to endogenous (IL-8) and bacterial (fMLP) chemoattractants, which was directly correlated with peripheral CD4⁺ lymphocyte levels but not plasma viral load. A similar chemotactic defect was observed in the feline immunodeficiency virus (FIV) model of HIV infection. Intravital microscopy of FIV-infected animals revealed marked impairment in the in vivo recruitment of leukocytes; specifically integrin-dependent neutrophil adhesion and emigration induced by bacterial products. Treatment of FIV-infected animals with GM-CSF re-established both neutrophil recruitment (rolling, adhesion, and emigration) and in vitro chemotaxis to the levels seen in uninfected animals. This restoration of neutrophil responses was not due to GM-CSF-mediated priming. Rather, HIV and FIV infections resulted in defective neutrophil development, with an ensuing reduction in neutrophil granularity and chemotactic receptor expression. GM-CSF therapy restored neutrophil granularity, implying restoration of normal neutrophil development. Together, our findings underscore the fundamental defects in innate immunity caused by lentivirus infections, while also indicating that GM-CSF may be a potential immunorestorative therapy for HIV-infected patients.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Canadian Institutes of Health Research (to P.K., C.B., and C.P.) and the National Institutes of Health (National Institute of Neurological Disorders and Stroke) (to C.P.). B.H. holds an Alberta Heritage Foundation for Medical Research studentship; G.J. holds a Canadian Institutes of Health Research Fellowship; J.M.A. holds an Alberta Heritage Foundation for Medical Research/Multiple Sclerosis Society of Canada studentship; C.P. holds a Canada Research Chair (Tier 1) in Neurological Infection and Immunity; and P.K. holds a Canada Research Chair (Tier 1) in Innate Immunity.

² Address correspondence and reprint requests to Dr. Paul Kubes, Immunology Research Group, University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta, Canada T2N 4N1. E-mail address: pkubes{at}ucalgary.ca

³ Abbreviations used in this paper: FIV, feline immunodeficiency virus; SMA, superior mesenteric artery.