BASIC MECHANISMS IN HTLV-INDUCED LEUKEMIA AND AIDS

逆转录病毒家族被称为人类T细胞嗜淋巴逆转录病毒 (HTLV-I、II和III)具有感染T淋巴细胞的亲和力和 相似的基因组结构。所有三种类型的HTLV都已在 体外、分子克隆和测序。尽管有这些进步，但 感染这些病毒导致恶性病变的机制 转化或免疫抑制仍不清楚。我们专注于 在细胞和分子水平上的基本机制 病毒会转化或抑制免疫。为了解决HTLV-I是否 可能通过插入突变机制诱导转化，我们 利用了啮齿动物细胞和 HTLV-I感染细胞株研究HTLV的过程和后果 染色体整合。体外整合被证明是一个动态的 过程和前病毒整合显然是随机发生在 基因组。目前正在进行研究，以确定共同整合是否 这些部位出现在新鲜的肿瘤材料中。由于HTLV-I感染细胞 经常失去对白细胞介素2(IL-2)的依赖，这种基因可能会发挥作用 在HTLV-I诱导转化中的作用该基因最先被定位到 4号染色体，在正常淋巴细胞中定位于4q26-28。我们是下一个 证明IL-2基因在几株HTLV-I中没有重排 感染细胞系，并定位到Hut 102的4号染色体上，表明 该基因在HTLV-I诱导的恶性转化中不起作用。我们 我还利用Hut 102X中国仓鼠杂交种的面板 证明新的第I类抗原决定簇在 HTLV-I感染细胞不是诱导I类基因的结果 由细胞MHC基因座编码，但可能由整合的 HTLV-I。包含在LtR中的启动子单位的活性 通过将HTLV-I和HTLV-III导入不同的细胞，检测HTLV-I和HTLV-III 含有与HTLV-I或HTLV-III连锁的HTLV-I或HTLV-III LTR的重组质粒 氯霉素乙酰转移酶(CAT)细菌基因。我们有 证明受感染的细胞含有作用于反式病毒的因子 感染病毒的转录因子来激活转录。

The family of retroviruses known as human T-cell lymphotropic retroviruses (HTLV-I, II, and III) has an affinity for infecting T lymphocytes and a similar genomic structure. All 3 types of HTLV 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 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. Studies are in progress to determine whether common integration sites are present in fresh tumor material. Since HTLV-I infected cells often lose their dependence for interleukin-2 (IL-2) this gene may play a role in transformation induced by HTLV-I. The gene was first mapped to chromosome 4 and sublocalized to 4q26-28 in normal lymphocytes. We next demonstrated that the IL-2 gene was not rearranged in several HTLV-I infected cell lines and mapped to chromosome 4 in Hut 102, suggesting that this gene is not operative in HTLV-I induced malignant transformation. We have also utilized the panel of Hut 102X Chinese hamster hybrids to demonstrate that the novel Class I antigenic determinants expressed on HTLV-I infected cells does 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.