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Journal of Virology, October 2001, p. 9703-9712, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9703-9712.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Endothelial Cells Enhance Human Immunodeficiency Virus Type 1 Replication in Macrophages through a C/EBP-Dependent Mechanism

Eileen S. Lee,1 Huiyu Zhou,1,dagger and Andrew J. Henderson1,2,*

Department of Veterinary Science2 and Graduate Program in Biochemistry, Microbiology and Molecular Biology,1 Pennsylvania State University, University Park, Pennsylvania 16802

Received 13 December 2000/Accepted 13 July 2001

Macrophages are early targets of human immunodeficiency virus type 1 (HIV-1) infection and serve as potential reservoirs for long-term infection. Through inflammatory mediators and direct cell contact, infected macrophages interact with neighboring cell populations, such as the endothelium, which create a microenvironment favorable for HIV-1 replication. We hypothesize that the transcriptional activator C/EBPbeta is critical for macrophages to respond to endothelial cell-derived signals. We show that endothelial cells significantly enhance C/EBPbeta binding activity and HIV-1 replication in macrophages. This increase in HIV-1 transcription is due to cell-cell contact as well as the production of soluble factors, mediated in part by ICAM-1 and interleukin 6, respectively. Furthermore, C/EBP factors are necessary for endothelial cell-dependent activation of HIV-1 transcription in macrophages, and HIV-1 induction can be inhibited by a C/EBP dominant-negative protein. In addition, C/EBP binding sites are necessary for efficient LTR activity and HIV-1 replication in the presence of endothelial cells. Taken together, these results indicate that endothelial cells, through the activation of C/EBPbeta , provide a microenvironment that supports HIV-1 replication in monocytes/macrophages.

* Corresponding author. Mailing address: Department of Veterinary Science, 115 Henning Building, Pennsylvania State University, University Park, PA 16801. Phone: (814) 863-0340. Fax: (814) 863-6140. E-mail: ajh6{at}psu.edu.

dagger Present address: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262.

Journal of Virology, October 2001, p. 9703-9712, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9703-9712.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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