SYNERGISTIC ACTIVATION OF SIMIAN IMMUNODEFICIENCY VIRUS AND HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TRANSCRIPTION BY RETINOIC ACID AND PHORBOL ESTER THROUGH AN NF-KAPPA-B-INDEPENDENT MECHANISM

The activation of human immunodeficiency virus type 1 (HIV-1) expressi on in latently infected cells by exogenous agents is believed to be im portant in the progression of AIDS. Most factors that are known to act ivate HIV-1 gene expression increase the binding of NF-kappa B or NF-k appa B-like transcription factors to the HIV-1 core enhancer region. I n this report, we demonstrate that retinoic acid (RA) treatment of pro monocytic U937 cells stimulates expression from the simian immunodefic iency virus (SIVmac) long terminal repeat (LTR). Furthermore, RA and p horbol 12-myristate 13-acetate (PMA) synergistically stimulated both S IVmac and HIV-1 LTRs to levels of expression comparable to that achiev ed by the viral transactivator Tat. The cis-acting elements required f or a response to RA and PMA cotreatment are located between nucleotide s -50 and +1 of SIVmac and between nucleotides -83 and +80 of HIV-1. T hus, the synergistic stimulation induced by RA and PMA is NF-kappa B i ndependent. Analysis of deletion mutants of the SIVmac LTR demonstrate s that RA and PMA stimulation cooperates with NF-kappa B and Sp1. An S IVmac LTR-reporter gene construct [pLTR(-50/+466)CAT] lacking NF-kappa B and Sp1 binding sites was not activated by Tat in untreated cells b ut was activated in cells that were cotreated with RA and PMA. Further more, gel retardation assays demonstrated that RA treatment causes a c hange in the pattern of a cellular factor(s) which binds to the -50 th rough +1 region of the SIVmac LTR. These data suggest that RA induces a PMA-activatable cellular factor that cooperates with NF-kappa B, Sp1 , or Tat to stimulate LTR-directed transcription.