Analysis of infection, integration and tumorigenesis of HTLV-1

此前，我们将HTLV-1产生细胞接种到新生小鼠体内，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却知之甚少。最近，我们成功地浓缩了保持感染活性的无细胞病毒，并建立了一个有效的无细胞感染系统。虽然有报道HTLV-1对小鼠细胞的感染性较低，但我们明确了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)。在人类载体中，关于HTLV-1前病毒载量控制因素的数据很少。我们利用我们建立的HTLV-1感染的小鼠模型，发现遗传背景作为HTLV-1前病毒载量的决定因素(BioChem.BiPhys.Res.Commun.309：161-165,2003)。为了阐明成人T细胞白血病的致癌机制，许多研究人员调查了Tax蛋白的功能。另一方面，为了研究插入突变的可能性，我们建立了反向聚合酶链式反应，并测定了HTLV-1在人类染色体上的精确整合位点。从23例ATL分离的25个HTLV-1整合位点中，有13个整合位点(52%)位于基因内，其整合频率明显高于随机整合的情况。有趣的是，一些基因与细胞生长的调节有关。这些结果与插入突变可能有助于HTLV-1感染细胞在ATL多阶段癌变过程中的克隆选择的想法并不冲突(癌症科学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).