Journal
JOURNAL OF VIROLOGY
Volume 86, Issue 15, Pages 7790-7805Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.07215-11
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Funding
- National Institutes of Health [RO1AI062248, RO1CA144043]
- Burroughs Wellcome Fund
- Rackham Merit Fellowship
- University of Michigan
- NIH Ruth L. Kirschstein NRSA Individual Predoctoral Fellowship [1F31CA150523-01]
- DHS Scholarship
- U.S. Department of Energy (DOE) [DE-AC05-00OR22750]
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Human endogenous retroviruses (HERVs) make up 8% of the human genome. The expression of HERV-K (HML-2), the family of HERVs that most recently entered the genome, is tightly regulated but becomes markedly increased after infection with HIV-1. To better understand the mechanisms involved in this activation, we explored the role of the HIV-1 Tat protein in inducing the expression of these endogenous retroviral genes. Administration of recombinant HIV-1 Tat protein caused a 13-fold increase in HERV-K (HML-2) gag RNA transcripts in Jurkat T cells and a 10-fold increase in primary lymphocytes, and the expression of the HERV-K (HML-2) rec and np9 oncogenes was also markedly increased. This activation was seen especially in lymphocytes and monocytic cells, the natural hosts for HIV-1 infection. Luciferase reporter gene assays demonstrated that the effect of Tat on HERV-K (HML-2) expression occurred at the level of the transcriptional promoter. The transcription factors NF-kappa B and NF-AT contribute to the Tat-induced activation of the promoter, as shown by chromatin immunoprecipitation assays, mutational analysis of the HERV-K (HML-2) long terminal repeat, and treatments with agents that inhibit NF-kappa B or NF-AT activation. These studies demonstrate that HIV-1 Tat plays an important role in activating expression of HERV-K (HML-2) in the setting of HIV-1 infection.
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