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

doi:10.1128/JVI.75.15.7067-7077.2001

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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^, 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 andbrain of individuals infected with human immunodeficiency virustype 1 (HIV-1) and is implicated in the pathogenesis of HIV-associateddementia (HAD). To explore the possible role of CXCL10/IP-10 inHAD, we examined the expression of this and other chemokines inthe central nervous system (CNS) of transgenic mice with astrocyte-targetedexpression of HIV gp120 under the control of the glial fibrillaryacidic protein (GFAP) promoter, a murine model for HIV-1 encephalopathy.Compared with wild-type controls, CNS expression of the CC chemokinegene CCL2/MCP-1 and the CXC chemokine genes CXCL10/IP-10 and CXCL9/Migwas induced in the GFAP-HIV gp120 mice. CXCL10/IP-10 RNA expressionwas increased most and overlapped the expression of the transgene-encodedHIV gp120 gene. Astrocytes and to a lesser extent microglia wereidentified as the major cellular sites for CXCL10/IP-10 gene expression.There was no detectable expression of any class of IFN or theirresponsive genes. In astrocyte cultures, soluble recombinant HIVgp120 protein was capable of directly inducing CXCL10/IP-10 geneexpression a process that was independent of STAT1. These findingshighlight a novel IFN- and STAT1-independent mechanism for theregulation of CXCL10/IP-10 expression and directly link expressionof HIV gp120 to the induction of CXCL10/IP-10 that is found inHIV infection of the CNS. Finally, one function of IP-10 expressionmay be the recruitment of leukocytes to the CNS, since the brainof GFAP-HIV gp120 mice had increased numbers of CD3⁺ T cells that were found in close proximity to sites of CXCL10/IP-10RNAexpression.

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

Manuscript 13725-NP from the Scripps ResearchInstitute.

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

^§ Present address: BioCytex, Marseille,France.

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