Establishment of an HTLV-I infection model by using human CRM1-transgenic rats

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Human T-cell leukemia virus type I (HTLV-I) has been known to cause adult T-cell leukemia (ATL) in infected individuals after a long incubation period, but the in vivo mechanism by which the virus causes the malignant transformation is largely unknown. In order to develop a suitable animal model for the investigation of HTLV-I-related leukemogenesis, in this study, we have examined in vivo proliferation of HTLV-I in rats carrying the human CRM1 (hCRM1) gene, which encodes a viral RNA transporter shown in vitro to be a species specific restriction factor between human and rat. The hCRM1-transgenic (Tg) rats were established from an F344/Slc rat. We have isolated several HTLY-1-infected T cell lines from Tg rats and found that production of Gag by T cells derived from Tg rats were significantly higher than that by wild type (Wt)-derived cells. We next assessed the proliferation of HTLV-I in Tg rats by inoculating HTLV-I-infected T cells. Analysis of plasma pl9 concentration in the infected rats over time did not show significant differences between Tg and Wt rats, although pl9 concentration in Tg rats tended to be higher in the first 4 weeks after infection. We also assessed the tissue distribution of HT LV-I provirus DNA at 1 week after intraperitoneal infection and found that the rate of the virus disseminated to thymus in Tg rats was significantly higher than that in Wt rats. However, we have not detected notable difference in HTLV-I proviral load between the two groups so far. Since we have observed significant enhancement of HTLV-I production in cells derived from Tg rats in vitro, the limited effects of hCRM1 observed in vivo study suggests that HT LV-I-specific immune responses may reduce the enhanced virus production in Tg rats.