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Journal of Virology, August 2001, p. 7067-7077, Vol. 75, No. 15
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.15.7067-7077.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Interferon-Independent, Human Immunodeficiency Virus Type 1 gp120-Mediated Induction of CXCL10/IP-10 Gene Expression by Astrocytes In Vivo and In Vitro†

Valérie C. Asensio,1,Dagger Joachim Maier,1 Richard Milner,1 Kaan Boztug,1 Carrie Kincaid,1 Maxime Moulard,2,§ Curtis Phillipson,1 Kristen Lindsley,1 Thomas Krucker,1 Howard S. Fox,1 and Iain L. Campbell1,*

Departments of Neuropharmacology1 and Immunology,2 The Scripps Research Institute, La Jolla, California

Received 1 December 2000/Accepted 20 April 2001

The CXC chemokine gamma interferon (IFN-gamma )-inducible protein CXCL10/IP-10 is markedly elevated in cerebrospinal fluid and brain of individuals infected 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 astrocyte-targeted expression of HIV gp120 under the control of the glial fibrillary acidic protein (GFAP) promoter, a murine model for HIV-1 encephalopathy. Compared with wild-type controls, CNS expression of the CC chemokine gene CCL2/MCP-1 and the CXC chemokine genes CXCL10/IP-10 and CXCL9/Mig was induced in the GFAP-HIV gp120 mice. CXCL10/IP-10 RNA expression was increased most and overlapped the expression of the transgene-encoded HIV gp120 gene. Astrocytes and to a lesser extent microglia were identified as the major cellular sites for CXCL10/IP-10 gene expression. There was no detectable expression of any class of IFN or their responsive genes. In astrocyte cultures, soluble recombinant HIV gp120 protein was capable of directly inducing CXCL10/IP-10 gene expression a process that was independent of STAT1. These findings highlight a novel IFN- and STAT1-independent mechanism for the regulation of CXCL10/IP-10 expression and directly link expression of HIV gp120 to the induction of CXCL10/IP-10 that is found in HIV infection of the CNS. Finally, one function of IP-10 expression may be the recruitment of leukocytes to the CNS, since the brain of GFAP-HIV gp120 mice had increased numbers of CD3+ T cells that were found in close proximity to sites of CXCL10/IP-10 RNA expression.

* Corresponding author. Mailing address: Department of Neuropharmacology, SP315, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-9306. Fax: (858) 784-9544. E-mail: icamp{at}scripps.edu.

dagger Manuscript 13725-NP from the Scripps Research Institute.

Dagger Present address: Digital Gene Technologies, La Jolla, Calif.

§ Present address: BioCytex, Marseille, France.

Journal of Virology, August 2001, p. 7067-7077, Vol. 75, No. 15
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.15.7067-7077.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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