Inhibition of herpesvirus-induced HIV-1 replication by cyclopentenone prostaglandins:: role of IκB kinase (IKK)

Objectives: Herpes simplex virus (HSV) infections have been associated with reactivation of HIV-1 replication and increases of HIV-1-load in plasma of co-infected individuals. The present authors have previously reported that in epithelial cells HSV-1 induces the IkappaB-kinase (IKK) causing persistent activation of NF-kappaB, a critical regulator of HIV-1 replication. The present study was performed to investigate whether HSV-1-infection could induce IKK-mediated NF-kappaB activation and enhance HIV-1 expression in human T cells, and to analyze the effect of the IKK-inhibitor prostaglandin A, (PGA(1)) and other prostanoids on the NF-kappaB-mediated HSV-HIV interaction. Design and methods: Induction of IKK and NF-kappaB activity was determined in lymphoblastoid Jurkat cells and HIV-1 chronically-infected H9 and ACH-2 cells by kinase assay and electrophoretic mobility shift assay, respectively. The effect of HSV-1 and different prostanoids on HIV-1 expression and replication was determined in Jurkat cells transfected with HIV-1-LTR-driven reporter genes, and in H9 and ACH-2 cells by p24-antigen level evaluation. The role of NF-kappaB in HSV-1-induced HIV-1 expression was investigated by using the IkappaBalpha dominant-negative IkappaBalpha-AA in cotransfection experiments. Results: In human T lymphoblastoid cells HSV-1 potently induces IKK activity, causing a persistent induction of NF-kappaB. HSV-1-induced IKK and NF-kappaB function results in transactivation of HIV-1-LTR-regulated genes and induction of HIV-1 replication in chronically-infected T cells. The cyclopentenone PGA(1) inhibits HSV-1-induced IKK and NF-kappaB activities, blocking HIV-1-LTR-driven expression and preventing HSV-1 -induced HIV-1 replication in co-infected cells. Conclusions: The results indicate that IKK is a key factor in triggering HSV-1 -induced HIV-1 transcription in chronically-infected cells and identify cyclopentenone prostanoids as potent inhibitors of HSV-1-induced HIV-1 reactivation. (C) 2004 Lippincott Williams Wilkins.