Differential effect of tumor necrosis factor-alpha and herpes simplex virus type 1 on the Tat-targeted inhibition of human immunodeficiency virus type 1 replication.Virology 1994; 202(2):521-9V
In this study, we have examined whether the Tat antagonist can inhibit human immunodeficiency virus type 1 (HIV-1) replication in the presence of cofactors that can activate transcription of HIV-1 provirus by an NF-kappa B-mediated mechanism, such as tumor necrosis factor-alpha (TNF-alpha) or herpes simplex virus type 1 (HSV-1) infection. As a prototype, we have chosen a low-molecular-weight Tat inhibitor, Ro5-3335, and analyzed its effect on HIV-1 replication in the presence of TNF-alpha and HSV-1 infection in acutely infected peripheral blood lymphocytes (PBLs) and T cells. Ro5-3335 inhibited HIV-1 replication both in CEM-174 cells and in PBLs, but the magnitude of the inhibition was inversely related to viral inoculum and the inhibition was only temporary; viral replication resumed at later times postinfection in spite of the continuous presence of the drug. In contrast, Ro5-3335 suppressed TNF-alpha-induced activation of HIV-1 replication in chronically infected T cells and monocytes that both expressed only low levels of HIV-1 constitutively, while its effect in high-expressing OM-10.1 cells was negligible in the presence of TNF-alpha. The inhibition of HIV-1 replication by Ro5-3335 was specific for the Tat-mediated effect and this drug was not able to inhibit the TNF-alpha-induced expression of the tat-defective HIV-1 provirus. In contrast to TNF-alpha, HSV-1-stimulated HIV-1 expression in the ACH-2 cells was effectively inhibited in the presence of Ro5-3335. These results demonstrate that Tat plays an essential role in HSV-1-mediated activation of HIV-1 provirus, while the TNF-alpha complementation of Tat shows cell-type specificity. These observations suggest that inhibition of the Tat function alone may not be sufficient for an effective anti-HIV-1 inhibition.