Key Points• Humanized mice, IBMIhuNOG, were generated by intra-bone marrow injection of human CD1331 hematopoietic stem cells.• HTLV-1-infected IBMIhuNOG mice recapitulated distinct ATL-like symptoms as well as HTLV-1-specific adaptive immune responses.Human T-cell leukemia virus type 1 (HTLV-1) is causally associated with adult T-cell leukemia (ATL), an aggressive T-cell malignancy with a poor prognosis. To elucidate ATL pathogenesis in vivo, a variety of animal models have been established; however, the mechanisms driving this disorder remain poorly understood due to deficiencies in each of these animal models. Here, we report a novel HTLV-1-infected humanized mouse model generated by intra-bone marrow injection of human CD133 1 stem cells into NOD/Shi-scid/IL-2Rgc null (NOG) mice (IBMI-huNOG mice).Upon infection, the number of CD4 1 human T cells in the periphery increased rapidly, and atypical lymphocytes with lobulated nuclei resembling ATL-specific flower cells were observed 4 to 5 months after infection. Proliferation was seen in both CD25 2 and CD25 1 CD4 T cells with identical proviral integration sites; however, a limited number of CD25 1 -infected T-cell clones eventually dominated, indicating an association between clonal selection of infected T cells and expression of CD25. Additionally, HTLV-1-specific adaptive immune responses were induced in infected mice and might be involved in the control of HTLV-1-infected cells. Thus, the HTLV-1-infected IBMI-huNOG mouse model successfully recapitulated the development of ATL and may serve as an important tool for investigating in vivo mechanisms of ATL leukemogenesis and evaluating anti-ATL drug and vaccine candidates. (Blood. 2014;123(3):346-355)

HTLV-1 infection of humanized NOG mice has been demonstrated to recapitulate the development of ATL-like symptoms within several months of infection. Infected human T-cells in these mice start to proliferate vigorously in a couple weeks after infection and the mice die of ALTlike lymphoproliferative disorder. Thus, this mouse model should provide a potent tool to analyze the in vivo effect of various candidates for ATL treatment.Treatment of ATL with the combination of anti-viral agents, zidovudine (AZT) and interferon-alpha (IFN), has been reported to be highly effective, especially to indolent type, but the mechanism of action is totally unknown. We, therefore, examined the efficacy and the in vivo mechanism of AZT/IFN treatment in the humanized mouse system.HTLV-1 infected humanized mice were inoculated daily with AZT and IFN from two to four weeks post infection and the number of infected cells and proviral loads (PVL) were analyzed. Treatment with either AZT or IFN alone attenuated the onset of lymphoproliferative disorder, whereas the combined treatment suppressed the growth of infected T-cells in PBL almost completely and the PVL remained low throughout lifetime. The suppressive effect is infected-cell specific because the number of uninfected human lymphocytes in PBL stayed constant on the administration of drugs.It is suggested that infected cells expressing higher level of viral gene, most provably Tax, should have been selectively eliminated, since a similar suppressive effect has been obtained in HTLV-1 infected humanized mice treated with an Hsp90 inhibitor, 17-DMAG, which enhances the degradation of Tax.

Ueno et al.: Altered pattern in viral mRNA expression of Iranian type HTLV-1 leading to enhanced viral expression.

No abstract

No abstract