Abstract
Background
This study was conducted to construct a basis for a therapeutic strategy against human T-lymphotropic virus type-I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) using a compound that contained a disulfide moiety, prosultiamine, which is a homologue of allithiamine originally synthesized by allicin and thiamine-thiol, for the targeting of HTLV-I-infected cells.
Methods
First, we analysed the apoptotic pathway in allicin or prosultiamine treatment against an HTLV-I-infected T-cell line (HCT-1), derived from an HAM/TSP patient, by flow cytometry and western blot. Second, we evaluated the effect of targeting HTLV-I-infected cells in a prosultiamine in vitro treatment and in a clinical trial in HAM/TSP patients by quantitative PCR analysis of HTLV-I proviral load.
Results
Prosultiamine, like allicin, induced caspase-dependent apoptosis against HCT-1 cells. The fact that the loss of mitochondrial membrane potential was recovered in z-VAD-fmk-pretreated HCT-1 cells with prosultiamine treatment suggested that prosultiamine can induce caspase-dependent apoptosis through the mitochondrial pathway. On the basis of data showing that prosultiamine in vitro treatment against peripheral blood CD4+ T-cells of HAM/TSP patients induced a significant decrease of HTLV-I proviral copy numbers by apoptosis of HTLV-I- infected cells, we treated six HAM/ TSP patients with intravenous administration of pro-sultiamine for 14 days. As a result of this treatment, the copy numbers of HTLV-I provirus in peripheral blood decreased to approximately 30–50% of their pretreat-ment levels with some clinical benefits in all patients.
Conclusions
Our results suggest that prosultiamine has the potential to be a new therapeutic tool that targets HTLV-I-infected cells in HAM/TSP.