INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION BY A BIOAVAILABLE SERINE THREONINE KINASE INHIBITOR, FASUDIL HYDROCHLORIDE/

Replication of human immunodeficiency virus type 1 (HIV-1) is regulate d by a host transcription factor, nuclear factor kappa B (NF-kappa B), NF-kappa B belongs to a group of inducible transcription factors and its activity is regulated by multiple cellular signal transduction pat hways, including kinases, These kinases are known to be involved in si gnal-induced NF-kappa B activation and in the induction of HIV-1 gene expression from latently infected cells, In this study me have examine d the effect of a newly developed serine/threonine kinase inhibitor, f asudil hydrochloride (FH), on the replication of HIV-1, Although FH wa s initially developed as a compound that inhibited a myosin light chai n kinase (MLCK) and had been approved for clinical use in the treatmen t of vasospasm after subarachnoid hemorrhage, this study shows its eff icacy in blocking HIV-1 replication in latently infected patients. Whe n FH was added to monocytic cell lines latently infected with HIV-1, U 1 and OM10.1, the induction of HIV-1 replication by TNF-alpha mas bloc ked at noncytotoxic doses, The IC50 values of HIV-1 induction by FH we re 9.3 and 24 mu M for U1 and OM10.1, respectively. Because FH could b lock TNF-alpha-induced, NF-kappa B-dependent gene expression, as exami ned by the transient luciferase expression assay, the effect of FH was considered to be due to the blocking of the signal transduction pathw ay of NF-KB activation, Although the in vivo effect of FH in blocking HIV-1 induction is not yet known, these findings indicate the feasibil ity of clinical use of FH and its derivatives in decreasing viral load to prevent clinical development of acquired immunodeficiency syndrome (AIDS) among HIV-1-infected individuals.