Pentosan Polysulfate Demonstrates Anti-human T-Cell Leukemia Virus Type 1 ActivitiesIn VitroandIn Vivo

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) infection causes T-cell leukemia and inflammatory diseases, most notably including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The underlying mechanism for the pathogenesis of HAM/TSP remains unclear. According to a recent clinical trial, a humanized antibody that targets CCR4 ϩ cells ameliorates inflammation by reducing the number of infected cells in the central nervous system; this result suggests that the transmigration of HTLV-1-infected cells plays a crucial role in HAM/TSP. Partly due to the blood-brain barrier, current treatments for HAM/TSP are mostly palliative. Pentosan polysulfate (PPS), a semisynthetic glycosaminoglycan, has recently been used to treat HAM/TSP and was found to alleviate the symptoms. In this study, we investigated the effect of PPS on HTLV-1-infected cells and provide evidence for its efficacy in HAM/TSP. PPS was cytotoxic to certain HTLV-1-infected cells and significantly suppressed HTLV-1 virion production. PPS also efficiently inhibited HTLV-1 cell-cell transmission in T cells. In addition, PPS blocked HTLV-1 infection of primary endothelial cells (human umbilical vascular endothelial cells) and suppressed the subsequent induction of proinflammatory cytokine expression. Furthermore, PPS was found to inhibit the adhesion and transmigration of HTLV-1-infected cells. We also confirmed the anti-HTLV-1 effect of PPS in vivo using two mouse models. PPS blocked HTLV-1 infection in a mouse model with peripheral blood mononuclear cell (PBMC)-humanized NOD-scid IL2Rgamma null (huPBMC NSG) mice. PPS was also found to suppress the development of dermatitis and lung damage in HTLV-1 bZIP factor (HBZ)-transgenic (HBZ-Tg) mice, an HTLV-1 transgenic mouse model in which the mice develop systemic inflammation. IMPORTANCE HTLV-1 is the first human retrovirus to have been identified and is endemic in certain areas worldwide. HTLV-1 infection leads to the development of an inflammatory disease called HAM/TSP, a myelopathy characterized by slowly progressive spastic paraparesis. There have been no effective therapeutics available for HAM/TSP, but recently, a semisynthetic glycosaminoglycan, named pentosan polysulfate (PPS), has been found to alleviate the symptoms of HAM/TSP. Here we conducted a comprehensive study on the effect of PPS both in vitro and in vivo. PPS demonstrated anti-HTLV-1 potential in infected cell lines, as shown by its suppressive effects on HTLV-1 replication and transmission and on the transmigration of infected T cells. Moreover, results obtained from two HTLV-1 mouse models demonstrate that PPS inhibits HTLV-1 infection and inflammation development in vivo. Our work offers insights into the treatment of HAM/TSP by PPS and also suggests its possible use for treating other HTLV-1-induced inflammatory diseases.

HTLV-1 activates YAP via NF-κB/p65 to promote oncogenesis

“…For the endogenous interaction between YAP and p65, ATL cell lysate was incubated with anti-YAP antibody (Cell Signaling Technology) or anti-mouse immunoglobulin G (IgG) (Santa Cruz Biotechnology), and the following procedures were the same as described above in 293T cells. Other antibodies used were as follows: anti-FLAG M2, anti-HA, anti–c-Myc (Sigma-Aldrich), anti-p65, anti–phospho-YAP (Ser127), anti–phospho-YAP (Ser381), anti-GAPDH (Cell Signaling Technology), and anti-Tax was used as previously described ( 51 ).…”

HTLV-1 targets human placental trophoblasts in seropositive pregnant women

“…Cells were then switched to serum-free Trophoblast Medium for 24 hours before incubation in the same medium with or without human recombinant IGF-1 (PeproTech) (20 or 200 ng/mL) for 24 hours, as previously described (46). To infect placental cells with HTLV-1, VTs, VMFs, and PVECs were cocultured with lethally irradiated HTLV-1-producing MT-2 cells as previously reported (47). On the next day of cocultivation, the cells were thoroughly washed with PBS to remove residual MT-2 cells.…”

“…We examined whether placental cells infected with HTLV-1 expressed viral antigens. Considering that HTLV-1 infection is spread by cell-to-cell transmission, a coculture model of HTLV-1-producing cells and target primary cells was employed (47). Target VTs, VMFs, and PVECs were cocultured with HTLV-1producing cells ( Figure 6A), and the expression level of viral envelope glycoprotein on the surface of the target cells was analyzed by flow cytometry.…”

Anti-inflammatory actions of Pentosan polysulfate sodium in a mouse model of influenza virus A/PR8/34-induced pulmonary inflammation

“…Early inhibition of viral attachment and entry represents a key advantage in acute disease management, and several antiviral drugs targeting these mechanisms have been developed and tested ( 10 , 41 , 42 ). PPS has been shown to inhibit human T-lymphotropic virus 1 (HTLV-1) replication in vitro ( 43 ), and recent studies indicate that PPS inhibits SARS-CoV-2 infection in vitro by modifying the receptor binding domain of S1 protein ( 44 , 45 ). We found that at 8 dpi, viral titers in the lungs of mice infected with PR8 were not affected by PPS treatment, with no differences observed between infected mice treated with vehicle or with 3 mg/kg PPS.…”