Dysregulation of signal transduction pathways as a potential mechanism of nervous system alterations in HIV-1 gp120 transgenic mice and humans with HIV-1 encephalitis.
HIV-1 associated central nervous system (CNS) disease involves neuronal damage and prominent reactive astrocytosis, the latter characterized by strong upregulation of the glial fibrillary acidic protein (GFAP) in astrocytes. Similar alterations are found in transgenic mice expressing the HIV-1 envelope protein gp120 in the CNS. Because alterations of astrocyte functions could contribute to neuronal impairment, we compared brains of gp120 transgenic mice and gp120-transfected C6 astrocytoma cells with controls and found that gp120 induced a prominent elevation of steady state GFAP mRNA levels, primarily due to transcript stabilization. Increased levels of GFAP mRNA were also found in nontransfected C6 cells exposed to recombinant gp120. Exposure of C6 cells or primary mouse astrocytes to soluble gp120 led to activation of PKC as indicated by redistribution and increase in PKC immunoreactivity at the single cell level. gp120 effects were diminished by inhibitors of protein kinase C (PKC) but not inhibitors of protein kinase A. PKC activity was upmodulated in gp120-transfected C6 cells and in the CNS of gp120 transgenic mice. Further, brain tissue from patients with HIV-1 encephalitis and from gp120 transgenic mice showed increased PKC immunoreactivity. Taken together, these results indicate that gp120-induced increases in PKC activity may contribute to the gliosis seen in gp120 transgenic mice as well as in HIV-1-infected humans and raise the question of whether dysregulation of signal transduction pathways represents a general mechanism of HIV-associated pathogenesis.
Wyss-Coray
T
T
Gladstone Molecular Neurobiology Program, University of California, San Francisco 94141-9100, USA.
Masliah
E
E
Toggas
S M
SM
Rockenstein
E M
EM
Brooker
M J
MJ
Lee
H S
HS
Mucke
L
L
D015526:AIDS Dementia Complex / Q000209:etiology*; D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000633:toxicity*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D015699:HIV Envelope Protein gp120; D012333:RNA, Messenger; D011493:Protein Kinase C