Compounds that target novel cellular components involved in HIV-1 transcription.

Abstract

BACKGROUND:

Therapeutic intervention designed to block expression of human immunodeficiency virus (HIV) at a cellular level may slow the clinical progression of HIV-1 disease.

MATERIALS AND METHODS:

Cellular models of latent (OM-10.1 and U1) and chronic (8E5) HIV infection were used to evaluate two benzothiophene derivatives, PD 121871 and PD 144795, for an ability to inhibit HIV activation and expression.

RESULTS:

The benzothiophene derivatives were effective at micromolar concentrations in preventing tumor necrosis factor alpha (TNF alpha)-induced HIV-1 expression in OM 10.1 and U1 cultures. These compounds inhibited the activation of HIV-1 transcription; however, this inhibition was selective in that another TNF alpha-induced response, the transcription of autocrine TNF alpha, was unaffected. Constitutive HIV-1 expression by chronically infected 8E5 cells was also significantly reduced when treated with these experimental compounds. In TNF alpha-treated OM-10.1 cultures, the inhibition of HIV-1 transcription by these compounds was not due to a block of nuclear factor-kappa B induction. The benzothiophene derivatives also inhibited HIV-1 activation by phorbol ester treatment of OM-10.1 promyelocytes, although no inhibition of cellular differentiation toward a macrophage-like phenotype was observed. Furthermore, these experimental compounds induced a state of HIV-1 latency in cytokine-activated OM-10.1 cultures even when maintained under constant TNF alpha stimulation. The benzothiophene derivatives did not inhibit the activity of the HIV-1 trans-activator, Tat, when evaluated in transient transfection assays.

CONCLUSIONS:

The benzothiophene derivatives appear to inhibit a critical cellular component, distinct from nuclear factor-kappa B, involved in HIV transcription and may serve to identify new therapeutic targets to restrict HIV expression.

• Authors: S T Butera, B D Roberts, J W Critchfield, G Fang, T McQuade, S J Gracheck, T M Folks
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 1 Issue 7 Pg. 758-67 (Nov 1995) ISSN: 1076-1551 [Print] England
• PMID: 8612198 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• NF-kappa B
• PD 121871
• Phorbol Esters
• Thiophenes
• Tumor Necrosis Factor-alpha
• PD 144795

Topics

• Antiviral Agents (pharmacology)
• Cell Line
• Dose-Response Relationship, Drug
• Drug Interactions
• HIV-1 (drug effects, genetics)
• NF-kappa B (metabolism)
• Phorbol Esters (pharmacology)
• Thiophenes (pharmacology)
• Transcription, Genetic (drug effects)
• Tumor Necrosis Factor-alpha (pharmacology)
• Virus Latency