BASIC MECHANISMS IN HTLV-INDUCED LEUKEMIA AND AIDS

T细胞嗜淋巴逆转录病毒(HTLV-I、II和III)具有 并通过与人T淋巴细胞的特异性相互作用进入细胞 T-4受体。这三种类型的HTLV都是在体外传播的， 分子克隆和测序。尽管取得了这些进展，但该机制通过 哪种感染这些病毒会导致恶变或 免疫抑制作用仍不清楚。我们关注的是基本机制， 在细胞和分子水平上，这些病毒通过这些改变或 免疫抑制。为了解决HTLV-I是否会导致 通过插入突变机制进行转化，我们有 利用啮齿动物细胞和鼠类细胞构建体细胞杂交 研究HTLV-I感染人细胞系的过程和后果 HTLV染色体整合。体外整合被证明是一种 动态过程和前驱整合显然是随机发生在 基因组。我们还利用了HUT 102 X中国仓鼠的面板 证明新型I类抗原决定簇的杂交体 HTLV-I感染细胞上的表达不是诱导I类基因的结果 由细胞MHC基因座编码的基因，但可能是由 集成HTLV-I。其中包含的启动子单元的活性 通过将HTLV-I和HTLV-III分别导入不同的病毒载体，检测HTLV-I和HTLV-III的LTR 含HTLV-I或HTLV-III LTR重组质粒的细胞 与氯霉素乙酰转移酶(CAT)的细菌基因连锁。 我们已经证明，受感染的细胞含有反式作用因子。 在感染病毒的ltrs上激活转录。两个家庭 内源性逆转录病毒序列被证明广泛分散在 利用基因分析技术分析人类基因组。这些序列的结果是 一种古老的进化基因扩增导致了超过 0.1%与逆转录病毒序列同源。

T-cell lymphotropic retroviruses (HTLV-I, II and III) have an affinity of human T lymphocytes and enter the cells by specific interaction with the T-4 receptor. All three types of HTLVs have been transmitted in vitro, molecularly cloned and sequenced. Despite these advances, the mechanism by which infection with these viruses results in malignant transformation or immunosuppression remains unknown. We are focusing on basic mechanisms, both on a cellular and molecular level, by which these viruses transform or immunosuppress. In order to address whether HTLV-I may induce transformation through an insertional mutagenesis mechanism, we have utilized somatic cell hybrids constructed between rodent cells and HTLV-I-infected human cell lines to study the processes and consequences of HTLV chromosomal integration. Integration in vitro was shown to be a dynamic process and proviral integration apparently occurs at random in the genome. We have also utilized the panel of Hut 102 X Chinese hamster hybrids to demonstrate that the novel Class I antigenic determinants expressed on HTLV-I-infected cells do not result from induction of Class I genes encoded by the cellular MHC locus, but are probably encoded by integrated HTLV-I. The activities of the promoter unit contained within the LTR of both HTLV-I and HTLV-III were examined by transfecting various cells with recombinant plasmids containing the LTR of HTLV-I or HTLV-III linked to the bacterial gene for chloramphenicol acetyltransferase (CAT). We have demonstrated that infected cells contain factors that act in trans on the LTRs of the infecting virus to activate transcription. Two families of endogenous retroviral sequences were shown to be widely dispersed in the human genome using genetic analysis. The sequences are the consequence of an ancient evolutionary gene amplification which resulted in greater than 0.1% being homologous to retroviral sequences.