Regulation of lentivirus neurovirulence by lipopolysaccharide conditioning: suppression of CXCL10 in the brain by IL-10.
Lentivirus infections including HIV and feline immunodeficiency virus (FIV) cause neurovirulence, which is largely mediated by innate immunity. To investigate the interactions between neurovirulence and repeated conditioning by innate immune activation, models of lentivirus infection were exposed to LPS. Gene expression in HIV-infected (HIV+) and control (HIV-) patient brains was compared by real time RT-PCR and immunocytochemistry. Supernatants from mock and HIV-infected monocyte-derived macrophages exposed to LPS were applied to human neurons. FIV-infected (FIV+) and control (FIV-) animals were exposed repeatedly to LPS postinfection together with concurrent neurobehavioral testing, viral load, and host gene analyses. Brains from HIV+ individuals exhibited induction of CD3epsilon, CXCL10, and granzyme A expression (p < 0.05). Supernatants from HIV+ monocyte-derived macrophages induced CXCL10 expression in neurons, which was diminished by IL-10 treatment (p < 0.05). LPS-exposed FIV+ animals demonstrated lower plasma and brain viral loads (p < 0.05). Neuronal CXCL10 expression was increased in FIV+ animals but was suppressed by LPS exposure, together with reduced brain CD3epsilon and granzyme A expression (p < 0.05). In conjunction with preserved NeuN-positive neuronal counts in parietal cortex (p < 0.05), FIV+ animals exposed to LPS also showed less severe neurobehavioral deficits (p < 0.05). Repeated LPS exposures suppressed CXCL10 in the brain and ensuing T cell infiltration with a concomitant reduction in neurovirulence. Thus, innate immune chronic conditioning exerted beneficial effects on neurovirulence through suppression of a specific chemotactic factor, CXCL10, mediated by IL-10, leading to reduced leukocyte infiltration and release of neurotoxic factors.
Maingat
Ferdinand
F
Division of Neurology, University of Alberta, Edmonton, Canada.
Viappiani
Serena
S
Zhu
Yu
Y
Vivithanaporn
Pornpun
P
Ellestad
Kristofor K
KK
Holden
Janet
J
Silva
Claudia
C
Power
Christopher
C
D000818:Animals; D001921:Brain / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002415:Cats; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors* / Q000502:physiology; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity*; D016753:Interleukin-10 / Q000502:physiology*; D016180:Lentivirus Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009474:Neurons / Q000276:immunology / Q000473:pathology / Q000821:virology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019562:Viral Load / Q000276:immunology; D014774:Virulence / Q000276:immunology
D054357:Chemokine CXCL10; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D016753:Interleukin-10