Dysregulation of mitogen-activated protein kinase signaling pathways in simian immunodeficiency virus encephalitis

Abstract

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.

Figure 1

Immunohistochemical analysis of brain sections derived from control and SIV-infected macaques. a: Quantitative immunohistochemical analysis of activated ERK (pERK); horizontal bars represent the means of each group. pERK expression was statistically different between control and 10-day groups (P = 0.019), 10-day and 21-day groups (P = 0.05), and control and 84-day groups (P = 0.01) b: Co-localization of pERK (purple) and GFAP (brown) in astrocytes (arrows) next to a capillary (arrowhead) in brain from a representative SIV-infected macaque at 10 days after inoculation. c: Co-localization of pERK (brown) and SIV gp41 (red) in macrophages (arrows) in the brain of a representative SIV-infected macaque at 10 days after inoculation. d: Quantitative immunohistochemical analysis of activated JNK (pJNK); horizontal bars represent the means of each group. pJNK expression was statistically different between 10-day and 21-day groups (P = 0.04) and 21-day and 84-day groups (P = 0.048). e: Co-localization of pJNK (blue) and CD68 (red) in macrophages (arrows) in brain from a representative SIV-infected macaque at 84 days after inoculation. f: Co-localization of pJNK (red) and SIV gp41 (blue) in perivascular macrophages (arrows and inset) in brain from a representative SIV-infected macaque at 84 days after inoculation. g: Quantitative immunohistochemical analysis of activated p38 (p-p38); horizontal bars represent the means of each group. p-p38 expression was statistically different between control and 21-day groups (P = 0.008) and control and 84-day groups (P = 0.022) h: Co-localization of p-p38 (red) and neuron-specific enolase (brown) in neurons (arrows) in brain from a representative SIV-infected macaque at 84 days after inoculation. i: Co-localization of p-p38 (red) and GFAP (brown) in astrocytes (arrows) in brain from a representative SIV-infected macaque at 84 days after inoculation. Arrowhead indicates an astrocyte that is not expressing p-p38.

Figure 2

Comparative expression of pERK (neuroprotective) versus pJNK and p-p38 (neurodegenerative) in brains of macaques during acute (10 days after inoculation), asymptomatic (21 and 56 days after inoculation), and terminal (84 days after inoculation) infection. Bars represent the net effect of neuroprotective and neurodegenerative influences based on percent change in expression of these signaling molecules, assuming that pERK, pJNK, and p-p38 have equal and independent influences. During acute infection, there was a net increase in expression of pERK, whereas during terminal infection neurodegenerative pathways, particularly p-p38, predominated.