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J Virol, August 1998, p. 6406-6413, Vol. 72, No. 8
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Binding of Human Immunodeficiency Virus Type 1 to CD4 and CXCR4 Receptors Differentially Regulates Expression of Inflammatory Genes and Activates the MEK/ERK Signaling Pathway

Waldemar Popik,1 Joseph E. Hesselgesser,2 and Paula M. Pitha1,3,*

Oncology Center1 and Department of Molecular and Genetics,3 The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, and Department of Immunology, Berlex Biosciences, Richmond, California 948042

Received 27 January 1998/Accepted 24 April 1998

We have previously shown that binding of human immunodeficiency virus type 1 (HIV-1) virions to CD4 receptors stimulates association of Lck with Raf-1 and results in the activation of Raf-1 kinase in a Ras-independent manner. In the present study, we demonstrate that HIV-1 envelope glycoproteins of both T-cell-tropic and macrophagetropic strains rapidly activate the ERK/mitogen-activated protein (MAP) kinase pathway and the binding of nuclear transcription factors (AP-1, NF-kappa B, and C/EBP) and stimulate expression of cytokine and chemokine genes. The activation of this signaling pathway requires functional CD4 receptors and is independent of binding to CXCR4. Binding of the natural ligand stromal cell-derived factor 1 (SDF-1) to CXCR4, which inhibits entry of T-cell-tropic HIV-1, activates also the ERK/MAP kinase pathway. However, SDF-1 did not affect the CD4-mediated expression of cytokine and chemokine genes. These results provide firm molecular evidence that binding of HIV-1 envelope glycoproteins to CD4 receptor initiates a signaling pathway(s) independent of the binding to the chemokine receptor that leads to the aberrant expression of inflammatory genes and may contribute significantly to HIV-1 replication as well as to deregulation of the immune system.

* Corresponding author. Mailing address: The Johns Hopkins University Oncology Center, 418 N. Bond St., Baltimore, MD 21231-1001. Phone: (410) 955-8871. Fax: (410) 955-0840. E-mail: parowe{at}welchlink.welch.jhu.edu.

J Virol, August 1998, p. 6406-6413, Vol. 72, No. 8
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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