Multiple Integrations of Human T-Lymphotropic Virus Type 1 Proviruses in the Engrafted Cells from the Asymptomatic Carriers in NOD/SCID/γc&lt;sup&gt;null&lt;/sup&gt; Mice

Yamamoto, Ikuo; Takajo, Ichiro; Umeki, Kazumi; Morishita, Kazuhiro; Hatakeyama, Kinta; Kataoka, Hiroaki; Nomura, Hajime; Okayama, Akira

doi:10.1159/000302760

Cited by 6 publications

(4 citation statements)

References 37 publications

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“…In this study, we used two mouse models to evaluate the effects of PPS on HTLV-1 in vivo. NSG mice have been found to support the engraftment of HTLV-1-infected cells due to their severely deficient immunity (66,67). Using NSG mice, we have also previously achieved establishment of a PBMC-humanized mouse model for HTLV-1 infection (55).…”

Section: Discussionmentioning

confidence: 99%

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

Yasunaga

Ohshima

et al. 2019

J Virol

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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.

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Section: Discussionmentioning

confidence: 99%

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

Yasunaga

Ohshima

et al. 2019

J Virol

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“…Of these HIV-1, EBV, dengue and HCV are by far the most widely studied and are discussed in more detail in sections below. Hu-Mice have also been used to study HTLV-1 proviral integration and induction of T cell lymphomas (Banerjee et al, 2010; Yamamoto et al, 2010; Villaudy et al, 2011). A number of studies focused on dengue viral infection and showed viremia with concomitant humoral and cellular responses (Kuruvilla et al, 2007; Cox et al, 2012; Jaiswal et al, 2012).…”

Section: Human Pathogens and Other Antigens Studied In Hu-micementioning

confidence: 99%

New generation humanized mice for virus research: Comparative aspects and future prospects

Akkina¹

2013

Virology

171

164

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Work with human specific viruses will greatly benefit from the use of an in vivo system that provides human target cells and tissues in a physiological setting. In this regard humanized mice (hu-Mice) have played an important role in our understanding of viral pathogenesis and testing of therapeutic strategies. Limitations with earlier versions of hu-Mice that lacked a functioning human immune system are currently being overcome. The new generation hu-Mouse models are capable of multilineage human hematopoiesis and generate T cells, B cells, macrophages and dendritic cells required for an adaptive human immune response. Now any human specific pathogen that can infect humanized mice can be studied in the context of ongoing infection and immune responses. Two leading humanized mouse models are currently employed: the hu-HSC model is created by transplantation of human hematopoietic stem cells (HSC), whereas the BLT mouse model is prepared by transplantation of human fetal liver, thymus and HSC. A number of human specific viruses such as HIV-1, dengue, EBV and HCV are being studied intensively in these systems. Both models permit infection by mucosal routes with viruses such as HIV-1 thus allowing transmission prevention studies. Cellular and humoral immune responses are seen in both the models. While there is efficient antigen specific IgM production, IgG responses are suboptimal due to inefficient immunoglobulin class switching. With the maturation of T cells occurring in the autologous human thymus, BLT mice permit human HLA restricted T cell responses in contrast to hu-HSC mice. However, the strength of the immune responses needs further improvement in both models to reach the levels seen in humans. The scope of hu-Mice use is further broadened by transplantation of additional tissues like human liver thus permitting immunopathogenesis studies on hepatotropic viruses such as HCV. Numerous studies that encompass antivirals, gene therapy, viral evolution, and the generation of human monoclonal antibodies have been conducted with promising results in these mice. For further improvement of the new hu-Mouse models, ongoing work is focused on generating new strains of immunodeficient mice transgenic for human HLA molecules to strengthen immune responses and human cytokines and growth factors to improve human cell reconstitution and their homeostatic maintenance.

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“…104 Successful transplantation of peripheral blood mononuclear cells (PBMCs) from NOG mice with primary HTLV-1 engraftment into a 2nd group of NOG mice resulted in a higher proviral load and multiple proviral integrations indicative of new infections. 105 The Hbz anti-sense viral transcript and protein has also been shown to enhance the proliferative capacity of HTLV-1-infected T cells in NOG mice. 13 SLB-1 cells, an HTLV-1 in vitro transformed cell line, with HBZ knockdown showed significantly reduced tumor formation and viral organ infiltration in NOG mice compared to wild-type SLB-1 cells.…”

Section: Mouse Modelmentioning

confidence: 99%

Animal Models Utilized in HTLV-1 Research

2013

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Since the isolation and discovery of human T-cell leukemia virus type 1 (HTLV-1) over 30 years ago, researchers have utilized animal models to study HTLV-1 transmission, viral persistence, virus-elicited immune responses, and HTLV-1-associated disease development (ATL, HAM/TSP). Non-human primates, rabbits, rats, and mice have all been used to help understand HTLV-1 biology and disease progression. Non-human primates offer a model system that is phylogenetically similar to humans for examining viral persistence. Viral transmission, persistence, and immune responses have been widely studied using New Zealand White rabbits. The advent of molecular clones of HTLV-1 has offered the opportunity to assess the importance of various viral genes in rabbits, non-human primates, and mice. Additionally, over-expression of viral genes using transgenic mice has helped uncover the importance of Tax and Hbz in the induction of lymphoma and other lymphocyte-mediated diseases. HTLV-1 inoculation of certain strains of rats results in histopathological features and clinical symptoms similar to that of humans with HAM/TSP. Transplantation of certain types of ATL cell lines in immunocompromised mice results in lymphoma. Recently, “humanized” mice have been used to model ATL development for the first time. Not all HTLV-1 animal models develop disease and those that do vary in consistency depending on the type of monkey, strain of rat, or even type of ATL cell line used. However, the progress made using animal models cannot be understated as it has led to insights into the mechanisms regulating viral replication, viral persistence, disease development, and, most importantly, model systems to test disease treatments.

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Multiple Integrations of Human T-Lymphotropic Virus Type 1 Proviruses in the Engrafted Cells from the Asymptomatic Carriers in NOD/SCID/γc<sup>null</sup> Mice

Cited by 6 publications

References 37 publications

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

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

New generation humanized mice for virus research: Comparative aspects and future prospects

Animal Models Utilized in HTLV-1 Research

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