Dysregulation of mitogen-activated protein kinase signaling pathways in simian immunodeficiency virus encephalitis.
Central nervous system (CNS) disease is a frequent complication of human immunodeficiency virus (HIV)-1 infection. Identification of cellular mechanisms that control virus replication and that mediate development of HIV-associated neuropathology will provide novel strategies for therapeutic intervention. The milieu of the CNS during HIV infection is extraordinarily complex because of infiltration of inflammatory cells and production of chemokines, cytokines, and neurotoxic molecules. Cells in the CNS must integrate signaling pathways activated simultaneously by products of virus replication and infiltrating immune cells. In this study, we examined activation of mitogen-activated protein kinases (MAPKs) in the CNS of simian immunodeficiency virus-infected macaques during acute, asymptomatic, and terminal infection. We demonstrate that significantly increased (P < 0.02) activation of ERK MAPK, typically associated with anti-apoptotic and neuroprotective pathways, occurs predominantly in astrocytes and immediately precedes suppression of virus replication and macrophage activation that occur after acute infection. In contrast, significantly increased activation of proapoptotic, neurodegenerative MAPKs JNK (P = 0.03; predominantly in macrophages/microglia), and p38 (P = 0.03; predominantly in neurons and astrocytes) after acute infection correlates with subsequent resurgent virus replication and development of neurological lesions. This shift from classically neuroprotective to neurodegenerative MAPK pathways suggests that agents that inhibit activation of JNK/p38 may be protective against HIV-associated CNS disease.
Barber
Sheila A
SA
Department of Comparative Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. sabarber@jhmi.edu
Uhrlaub
Jennifer L
JL
DeWitt
Jesse B
JB
Tarwater
Patrick M
PM
Zink
M Christine
MC
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology / Q000821:virology; D004660:Encephalitis / Q000821:virology*; D004789:Enzyme Activation / Q000502:physiology*; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008251:Macaca; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000201:enzymology*; D015302:Simian Immunodeficiency Virus / Q000201:enzymology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases
D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases