Analysis of infection, integration and tumorigenesis of HTLV-1

以前我们将HTLV-1产生细胞接种到新生小鼠中，并证明了人T细胞白血病病毒1型（HTLV-1）可以感染小鼠。然而，病毒增殖和宿主-病毒相互作用的过程知之甚少。最近，我们成功地浓缩了无细胞病毒，保留了感染活性，并建立了一个有效的无细胞感染系统。尽管报道了HTLV-1对小鼠细胞具有低感染性，但我们阐明了HTLV-1能够在该系统中有效地进入小鼠细胞（Jap.J.Cancer Res.93：760-766，2002）。我们使用了我们已经建立的HTLV-1感染的小鼠模型，发现遗传背景是HTLV-1前病毒载量的决定因素（Biochem.Biopharm.Res.Commun.309：161-165，2003）。另一方面，为了研究HTLV-1基因插入突变的可能性，我们建立了反向PCR技术，并对HTLV-1基因在人染色体上的整合位点进行了精确的定位。从23例ATL中分离到的25个HTLV-1整合位点中，有13个（52%）位于基因内，其整合率明显高于随机整合。有趣的是，一些基因与细胞生长的调控有关。这些结果与插入诱变可能有助于ATL多阶段致癌过程中HTLV-1感染细胞的克隆选择的观点不相冲突（Cancer Sci.95：306-310，2004）。

Previously we inoculated HTLV-1 producing cells into newborn mice and demonstrated that Human T-cell Leukemia Virus Type 1 (HTLV-1) could infect mouse. However, the process of viral proliferation and host-virus interaction is poorly understood. Recently we have succeeded in concentrating cell-free virus that retained infectious activity and established an efficient cell-free infection system. Although it was reported that HTLV-1 had low infectivity to mouse cells, we clarified HTLV-1 was able to entry into mouse cells efficiently in this system (Jap.J.Cancer Res.93 : 760-766, 2002).In human carrier, there are little data available on the factors controlling HTLV-1 proviral load. We employed a mouse model of HTLV-1 infection that we had established and found the genetic background as a determinant of HTLV-1 proviral load (Biochem.Biophys.Res.Commun.309 : 161-165, 2003).To clarify the mechanism of carcinogenesis in adult T-cell leukemia, many investigators surveyed the function of Tax protein. On the other hand, in order to investigate the possibility of insertional mutagesesis, we developed the inverse PCR and determined the precise HTLV-1 integration sites on human chromosome. Thirteen of the integration sites (52%) out of isolated 25 integration sites of HTLV-1 from 23 cases of ATL were within genes and the rate were significantly higher than that expected in the case of random integration. Interestingly, some of genes were related to the regulation of cell growth. These results did not conflict of the idea that insertional mutagenesis might contribute to the clonal selection of HTLV-1 infected cells during multistage carcinogenesis of ATL (Cancer Sci.95 : 306-310, 2004).