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 regulated by a host transcription factor, nuclear factor κB (NF-κB). NF-κB belongs to a group of inducible transcription factors and its activity is regulated by multiple cellular signal transduction pathways, including kinases. These kinases are known to be involved in signal-induced NF-κB activation and in the induction of HIV-1 gene expression from latently infected cells. In this study we have examined the effect of a newly developed serine/threonine kinase inhibitor, fasudil hydrochloride (FH), on the replication of HIV-1. Although FH was initially developed as a compound that inhibited a myosin light chain kinase (MLCK) and had been approved for clinical use in the treatment of vasospasm after subarachnoid hemorrhage, this study shows its efficacy in blocking HIV-1 replication in latently infected patients. When FH was added to monocytic cell lines latently infected with HIV-1, U1 and OM10.1, the induction of HIV-1 replication by TNF-α was blocked at noncytotoxic doses. The IC₅₀ values of HIV-1 induction by FH were 9.3 and 24 μM for U1 and OM10.1, respectively. Because FH could block TNF-α-induced, NF-κB-dependent gene expression, as examined by the transient luciferase expression assay, the effect of FH was considered to be due to the blocking of the signal transduction pathway of NF-κB activation. Although the in vivo effect of FH in blocking HIV-1 induction is not yet known, these findings indicate the feasibility 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.