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J Biol Chem, Vol. 273, Issue 13, 7431-7440, March 27, 1998

Inducible Expression of IB Repressor Mutants Interferes with NF-B Activity and HIV-1 Replication in Jurkat T Cells

Hakju Kwon^§, Nadine Pelletier^§, Carmela DeLuca^§, Pierre Genin^§, Sonia Cisternas, Rongtuan Lin^§, Mark A. Wainberg^§¶, and John Hiscott^§¶

From the  Lady Davis Institute for Medical Research and Departments of ^¶ Microbiology and ^§ Medicine,  McGill AIDS Center, McGill University, Montreal, Quebec H3T 1E2, Canada

Human immunodeficiency virus (HIV-1) utilizes the NF-B/Rel proteins to regulate transcription through NF-B binding sites in the HIV-1 long terminal repeat (LTR). Normally, NF-B is retained in the cytoplasm by inhibitory IB proteins; after stimulation by multiple activators including viruses, IB is phosphorylated and degraded, resulting in NF-B release. In the present study, we examined the effect of tetracycline-inducible expression of transdominant repressors of IB (TD-IB) on HIV-1 multiplication using stably selected Jurkat T cells. TD-IB was inducibly expressed as early as 3 h after doxycycline addition and dramatically reduced both NF-B DNA binding activity and LTR-directed gene activity. Interestingly, induced TD-IB expression also decreased endogenous IB expression to undetectable levels by 24 h after induction, demonstrating that TD-IB repressed endogenous NF-B-dependent gene transcription. TD-IB expression also sensitized Jurkat cells to tumor necrosis factor-induced apoptosis. De novo HIV-1 infection of Jurkat cells was dramatically altered by TD-IB induction, resulting in inhibition of HIV-1 multiplication, as measured by p24 antigen, reverse transcriptase, and viral RNA. Given the multiple functions of the NF-B/IB pathway, TD-IB expression may interfere with HIV-1 multiplication at several levels: LTR-mediated transcription, Rev-mediated export of viral RNA, inhibition of HIV-1-induced pro-inflammatory cytokines, and increased sensitivity of HIV-1-infected cells to apoptosis.

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