Cooperative inhibition of NF-kappa B and Tat-induced superactivation of human immunodeficiency virus type 1 long terminal repeat.
Human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)-regulated gene expression is stimulated independently by the cellular trans-activator NF-kappa B and the viral protein Tat. Noncytotoxic concentrations of the drug pentoxifylline (PTX) inhibited interaction of NF-kappa B with its motif and the stimulation of HIV-1 LTR-driven gene expression in Jurkat cells. Tat protein (from a cotransfected Tat-expression vector) also induced activation of HIV-1 LTR-driven gene expression. This activation was unaffected by PTX when NF-kappa B sites in the HIV-1 LTR were mutated, suggesting that this drug does not directly influence Tat function, which, however, was inhibited by the Tat-inhibitor Ro 24-7429. Transient reporter gene expression regulated by HIV-1 LTR with wild-type NF-kappa B motifs in the presence of Tat protein was 10- to 60-fold higher than in the presence of either of the trans-activators alone, demonstrating superactivation of HIV-1 LTR by the concerted action of both the trans-activators. Treatment of cells with either PTX or Ro 24-7429 inhibited this superactivation of the HIV-1 LTR. The inhibitory effect of these two drugs in combination, at concentrations that alone did not significantly influence viral promoter activity, was far more than additive. A cooperative action of PTX (NF-kappa B inhibitor) and Ro 24-7429 (Tat inhibitor) on HIV-1 LTR-regulated gene expression is suggested. Concentrations of the drugs that induced maximum inhibition of HIV-1 LTR through their cooperative action are far below cytotoxic levels. Thus, the combination of these two inhibitors could be very effective for anti-HIV therapy.
Biswas
D K
DK
Division of Cell Growth and Regulation, Dana-Farber Cancer Institute, Boston, MA.
Ahlers
C M
CM
Dezube
B J
BJ
Pardee
A B
AB
D000998:Antiviral Agents; D001569:Benzodiazepines / Q000008:administration & dosage*; D002460:Cell Line; D004357:Drug Synergism; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D015696:Gene Products, tat / Q000037:antagonists & inhibitors*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010431:Pentoxifylline / Q000008:administration & dosage*; D011758:Pyrroles; D054322:tat Gene Products, Human Immunodeficiency Virus
D000998:Antiviral Agents; D015696:Gene Products, tat; D016328:NF-kappa B; D011758:Pyrroles; D054322:tat Gene Products, Human Immunodeficiency Virus; D001569:Benzodiazepines; C070024:Ro 24-7429; D010431:Pentoxifylline