Interferon-independent, human immunodeficiency virus type 1 gp120-mediatedinduction of CXCL10/IP-10 gene expression by astrocytes in vivo and in vitro

The CXC chemokine gamma interferon (IFN-gamma)-inducible protein CXCL10/IP- 10 is markedly elevated in cerebrospinal fluid and brain of individuals inf ected with human immunodeficiency virus type 1 (HIV-1) and is implicated in the pathogenesis of HIV-associated dementia (HAD), To explore the possible role of CXCL10/ IP-10 in HAD, we examined the expression of this and other chemokines in the central nervous system (CNS) of transgenic mice with ast rocyte-targeted expression of HIV gp120 under the control of the glial fibr illary acidic protein (GFAP) promoter, a murine model for HIV-1 encephalopa thy, Compared with wild-type controls, CNS expression of the CC chemokine g ene CCL2/MCP-1 and the CXC chemokine genes CXCL10/IP-10 and CXCL9/Mig was i nduced in the GFAP-HIV gp120 mice. CXCL10/IP-10 RNA expression was increase d most and overlapped the expression of the transgene-encoded HIV gp120 gen e. Astrocytes and to a lesser extent microglia were identified as the major cellular sites for CXCL10/IP-10 gene expression. There was no detectable e xpression of any class of IFN or their responsive genes. In astrocyte cultu res, soluble recombinant HIV gp120 protein was capable of directly inducing CXCL10/IP-10 gene expression a process that was independent of STAT1. Thes e findings highlight a novel IFN- and STAT1-independent mechanism for the r egulation of CXCL10/IP-10 expression and directly link expression of HN gp1 20 to the induction of CXCL10/IP-10 that is found in HIV infection of the C NS, Finally, one function of IP-10 expression may be the recruitment of leu kocytes to the CNS, since the brain of GFAP-HIV gp120 mice had increased nu mbers of CD3(+) T cells that were found in close proximity to sites of CXCL 10/IP-10 RNA expression.