Replication of human immunodeficiency virus type 1 (HIV-1) is regulated by a host
transcription factor,
nuclear factor kappaB (
NF-kappaB).
NF-kappaB 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-kappaB 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-alpha was blocked at noncytotoxic doses. The IC50 values of HIV-1 induction by FH were 9.3 and 24 microM for U1 and OM10.1, respectively. Because FH could block
TNF-alpha-induced,
NF-kappaB-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-kappaB 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.