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.
andDepartment 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/EBP
is critical for macrophages to respond to endothelial cell-derived signals. We show that endothelial cells significantly enhance C/EBP
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/EBP
, provide a microenvironment that supports HIV-1
replication in monocytes/macrophages.
Present address: Department of Pharmaceutical Sciences, School of
Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262.
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