COMPOUNDS THAT TARGET NOVEL CELLULAR-COMPONENTS INVOLVED IN HIV-1 TRANSCRIPTION

Background: Therapeutic intervention designed to block expression of h uman immunodeficiency virus (HIV) at a cellular level may slow the cli nical progression of HIV-1 disease. Materials and Methods: Cellular mo dels of latent (OM-10.1 and U1) and chronic (8E5) HIV infection were u sed to evaluate two benzothiophene derivatives, PD 121871 and PD 14479 5, for an ability to inhibit HIV activation and expression. Results: T he benzothiophene derivatives were effective at micromolar concentrati ons in preventing tumor ne factor alpha (TNF alpha)-induced HIV-1 expr ession in OM-10.1 and U1 cultures. These compounds inhibited the activ ation of HIV-1 transcription; however, this inhibition was selective i n that another TNF alpha-induced response, the transcription of autocr ine TNF alpha, was unaffected. Constitutive HIV-1 expression by chroni cally infected 8E5 cells was also significantly reduced when treated w ith these experimental compounds. In TNF alpha-treated OM-10.1 culture s, the inhibition of HIV-I transcription by these compounds was not du e to a block of nuclear factor-kappa B induction. The benzothiophene d erivatives also inhibited HIV-1 activation by phorbol ester treatment of OM-10.1 promyelocytes, although no inhibition of cellular different iation toward a macrophagelike phenotype was observed. Furthermore, th ese experimental compounds induced a state of HIV-1 latency in cytokin e-activated OM-10.1 cultures even when maintained under constant TNF a lpha stimulation. The benzothiophene derivatives did not inhibit the a ctivity of the HIV-1 trans-activator, Tat, when evaluated in transient transfection assays. Conclusions: The benzothiophene derivatives appe ar to inhibit a critical cellular component, distinct from nuclear fac tor-kappa B, involved in HIV transcription and may serve to identify n ew therapeutic targets to restrict HIV expression.