Enhanced Replication of Human T-Cell Leukemia Virus Type 1 in T Cells from Transgenic Rats Expressing Human CRM1 That Is Regulated in a Natural Manner

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL).To develop a better animal model for the investigation of HTLV-1 infection, we established a transgenic (Tg) rat carrying the human CRM1 (hCRM1) gene, which encodes a viral RNA transporter that is a species-specific restriction factor. At first we found that CRM1 expression is elaborately regulated through a pathway involving protein kinase C during lymphocyte activation, initially by posttranscriptional and subsequently by transcriptional mechanisms. This fact led us to use an hCRM1-containing bacterial artificial chromosome clone, which would harbor the entire regulatory and coding regions of the CRM1 gene. The Tg rats expressed hCRM1 protein in a manner similar to expression of intrinsic rat CRM1 in various organs. HTLV-1-infected T-cell lines derived from these Tg rats produced 100-to 10,000-fold more HTLV-1 than did T cells from wild-type rats, and the absolute levels of HTLV-1 were similar to those produced by human T cells. We also observed enhancement of the dissemination of HTLV-1 to the thymus in the Tg rats after intraperitoneal inoculation, although the proviral loads were low in both wild-type and Tg rats. These results support the essential role of hCRM1 in proper HTLV-1 replication and suggest the importance of this Tg rat as an animal model for HTLV-1.

Nuclear and cytoplasmic effects of human CRM1 on HIV-1 production in rat cells

“…Thus, rat CRM1 represents a major factor in the human–rat species barrier to HTLV‐1 (Zhang et al. 2006; Takayanagi et al. 2007).…”

“…This results in the breakdown of HTLV-1 RNA transport in rat cells (Hakata et al 2001). Thus, rat CRM1 represents a major factor in the human-rat species barrier to HTLV-1 (Zhang et al 2006;Takayanagi et al 2007). Furthermore, detailed comparisons of human and rat CRM1 proteins identified the domains essential for the induction of Rex multimerization and the binding of RanBP3, another component involved in RNA export (Hakata et al 2003).…”

HIV‐1 susceptibility of transgenic rat‐derived primary macrophage/T cells and a T cell line that express human receptors, CyclinT1 and CRM1 genes

“…The hCRM1 Tg rat was described previously (Takayanagi et al 2007). Double Tg rats expressing hCD4 and hCycT1 were developed by simultaneous microinjection of a plasmid (which harbors hCD4 cDNA driven by CD4 regulatory sequences including the murine CD4 enhancer, hCD4 intron 1, and hCD4 promoter) (Killeen et al 1993) into fertilized F344 rat eggs and a BAC clone that harbors genomic hCycT1 (Okada et al 2009).…”

“…These lines were then mated together and with the hCRM1 Tg rat constructed previously (Takayanagi et al 2007) to develop progeny (designated F54YXM) that express all five human antigens: hCD4, hCCR5, hCXCR4, hCycT1, and hCRM1. These lines were then mated together and with the hCRM1 Tg rat constructed previously (Takayanagi et al 2007) to develop progeny (designated F54YXM) that express all five human antigens: hCD4, hCCR5, hCXCR4, hCycT1, and hCRM1.…”

“…In this study, we constructed three lines of Tg rat expressing either hCCR5 or hCXCR4, or doubly expressing hCD4/hCycT1 (designated F4Y). These lines were then mated together and with the hCRM1 Tg rat constructed previously (Takayanagi et al 2007) to develop progeny (designated F54YXM) that express all five human antigens: hCD4, hCCR5, hCXCR4, hCycT1, and hCRM1.…”