Endothelial cells enhance human immunodeficiency virus type 1 replication in macrophages through a C/EBP-dependent mechanism.
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.
Lee
E S
ES
Graduate Program in Biochemistry, Microbiology and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Zhou
H
H
Henderson
A J
AJ
D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D008264:Macrophages / Q000821:virology*; D011485:Protein Binding; D014779:Virus Replication
D022782:CCAAT-Enhancer-Binding Protein-beta; D015850:Interleukin-6; D018799:Intercellular Adhesion Molecule-1