HIV and other lentiviral infections cause defects in neutrophil chemotaxis, recruitment, and cell structure: immunorestorative effects of granulocyte-macrophage colony-stimulating factor.
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.
Heit
Bryan
B
Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta, Canada T2N 4N1.
Jones
Gareth
G
Knight
Derrice
D
Antony
Joseph M
JM
Gill
M John
MJ
Brown
Christopher
C
Power
Christopher
C
Kubes
Paul
P
D000818:Animals; D002415:Cats; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D045142:Cross-Priming; D003594:Cytoplasmic Granules / Q000648:ultrastructure; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D016089:Immunodeficiency Virus, Feline; D016209:Interleukin-8 / Q000494:pharmacology; D016180:Lentivirus Infections / Q000188:drug therapy / Q000276:immunology / Q000662:veterinary; D008070:Lipopolysaccharides / Q000276:immunology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000648:ultrastructure
D016209:Interleukin-8; D008070:Lipopolysaccharides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor