Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 385, Issue 1, Pages 100-105Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2009.04.156
Keywords
HIV-1; Bortezomib; Proteasome inhibitor; NF-kappa B; Itk; LTR; Transcription
Categories
Funding
- Swedish Cancer Fund
- Wallenberg Foundation
- Swedish Research Council
- Swedish International Development Cooperation Agency/Department for Research Cooperation
- EU FP6 EUROPRISE
- Swedish Foundation for Strategic Research
- Swedish Hemophilia Society
- Stockholm County Council
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HIV-1 has proved to be notoriously difficult to tackle despite the availability of more than 20 clinically approved drugs. The majority of these drugs, however, target viral genes and their continued use will select for drug-resistant strains. Since NF-kappa B signaling is critical for viral replication, we wanted to investigate the effect of proteasome inhibitors on viral gene expression. We herein demonstrate that proteasome and NF-kappa B inhibitors effectively shut down transcription from the HIV-1 LTR-promoter. We further show that replication of HIV-1 in PBMC was severely compromised following treatment with proteasome inhibitors alone or in combination with other antiretroviral drugs. Finally, incubation of PBMC with these drugs reduced expression of IL-2 inducible T cell kinase (Itk), a Tec-family kinase, recently shown to be required for HIV-1 replication. These results suggest that proteasome inhibitors suppress LTR-promoter activity by interfering with cellular targets required for viral replication. (C) 2009 Elsevier Inc. All rights reserved.
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