HIV-1 envelope protein gp41 modulates expression of interleukin-10 and chemokine receptors on monocytes, astrocytes and neurones.

Abstract

To analyse the effect of HIV-1 transmembrane protein gp41 on cytokine production and chemokine receptor expression in blood and brain. Because previous results had demonstrated that recombinant gp41 contributes to HIV-induced dysfunction of blood immune cells we investigated its effect on interleukin (IL)-10 synthesis and expression of the HIV coreceptors CCR5 and CXCR4 in different human brain cells. Astrocytic, microglial and neuronal cell lines were incubated with the extracellular domain of gp41 (aa565-647). Secretion of IL-10 into the medium was measured by ELISA. Chemokine receptor expression was analysed by fluorescence activated cell sorting and by RT-PCR. Incubation of the astrocytic cell line U87 with gp41 induced more than a 10 fold up-regulation of IL-10 secretion. This modulation was shown to be time- and dose-dependent. Use of inhibitors for different signal transduction pathways indicated a similar transduction cascade for the alteration of IL-10 production in astrocytes as in monocytes with participation of cAMP/adenylate cyclase and activation of p70S6 kinase. To a lesser extent IL-10 synthesis was also up-regulated by gp41 in the neuronal cell line SK-N-SH. In all cell types up-regulation of IL-10 paralleled by an enhanced expression of the chemokine receptor and HIV-1 coreceptor CCR5. This up-regulation was driven by IL-10 as shown by use of an IL-10 antibody. Expression of the chemokine receptor CXCR4 was only slightly altered. These findings suggest a role for gp41 in the modulation of brain-specific host defence, cell migration and cell infectivity by HIV.