HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinasesignaling pathway
D. Misse et al., HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinasesignaling pathway, BLOOD, 98(3), 2001, pp. 541-547
It has been previously shown that the HIV-1 envelope glycoprotein 120 (gp12
0) activates cell signaling by CXCR4, independently of CD4. The present stu
dy examines the involvement of different intracellular signaling pathways a
nd their physiopathologic consequences following the CD4-independent intera
ction between CXCR4 or CCR5 and gp120 in different cell types: primary T ce
lls, CD4(-)/ CXCR4(+)/CCR5(+) T cells, or glioma cells. These interactions
were compared with those obtained with natural ligands, stromal cell-derive
d factor 1 alpha (SDIF-1 alpha) (CXCL12) and macrophage inflammatory protei
n 1 beta (MIP-1 beta) (CCL4) of their respective coreceptors. Thus, both p3
8 and SAPK/Jun N-terminal kinase mitogen-activated protein kinases (MAPKs)
are activated on stimulation of these cells with either T- or M-tropic gp12
0, as well as with SDF-1 alpha. or MIP-1 beta. In contrast, extracellular s
ignal-related kinase 1 and 2 MAPKs are only activated by MIP-1 beta but not
by M-tropic gp120. Importantly, T- and M-tropic gp120 are able to induce t
he secretion of matrix metalloproteinase 9 (MMP-9), an extracellular metall
oproteinase present In cerebrospinal fluid of patients with HIV-1 by T cell
s or glioma cells. Specific inhibition of MAPK p38 activation resulted in a
complete abrogation of the induction of the MMP-9 pathogenic factor expres
sion by gp120 or chemokines in both cell types. Because neurodegenerative f
eatures in acquired Immune deficiency syndrome dementia may involve demyeli
nization by MMP-9, the specific targeting of p38 could provide a novel mean
s to control HIV-induced cytopathogenic effects and cell homing to viral re
plication sites.