GENETIC STRUCTURE OF MURINE RETROVIRUSES

鼠逆转录病毒的遗传结构

• 批准号: 3790705
• 负责人: L H EVANS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3790705
• 关键词: Retroviridae; Retroviridae disease; genetic polymorphism; genetic recombination; genetic strain; immunotherapy; immunotoxicity; laboratory mouse; mouse sarcoma virus; nonhuman therapy evaluation; nucleic acid sequence; point mutation; virus RNA; virus antigen; virus genetics; virus replication; virus virus interaction

Genetic variation is a hallmark of retrovirus infection and occurs in avian, murine and human retroviruses such as HIV. The major focus of this project is the study of genetic variation in retroviruses and the effect of such variation on virus infection and disease. Studies currently underway in the laboratory include the determination of the point mutation rate of retroviruses; the polymorphism of recombinant host range retrovirus variants; pseudotyping as a result of mixed retrovirus infections; and the treatment of retrovirus infections with immunotoxins reactive with retrovirus-coded antigens. A. Reported estimates of mutation rates of retroviruses suggest that progeny retroviruses sustain several point mutations during a replication cycle. In contrast we have determined that most progeny murine retroviruses do not sustain any point mutations during a single cycle. Studies are underway to compare the point mutation rate of viable progeny viruses to that of proviruses in the absence of selection for viability. B. Inoculation of many murine retroviruses in mice results in the generation of host range variants by recombination of the inoculated virus with endogenous retroviral genes. We have identified two major antigenic subgroups of these variants. The subgroups appear to be derived from distinct endogenous sequences and differ with respect to their in vitro cell tropisms. We are currently constructing chimeric viruses between viruses of the two major subgroups to map the genetic determinants of their properties. C. The generation of host range variants in retrovirus-infected mice results in a mixed retrovirus infection which may give rise to viral pseudotyping. We have found this to be the case in mice infected with the Moloney lymphocytic leukemia virus. Moreover, the pseudotyping appears to be a dynamic phenomenon which varies in different organs, changes during the course of disease and may influence the spread of infection of the target organ by host range variants. Continuing studies will examine the extent of virus spread and the cell-types infected by the host range variants. D. Ricin A-chain immunotoxins constructed using antibodies reactive with murine retrovirus-coded proteins have been tested for efficacy in selectively killing infected cells. Several immunotoxins have been found to be effective using infected in vitro cell lines. Initial studies using a murine retrovirus-induced neurodegenerative disease as a therapeutic model suggest that certain of the immunotoxins are also cytotoxic to infected cells in vivo. A retrovirus-induced lymphocytic leukemia is currently being evaluated as a second in vivo therapeutic model.

遗传变异是逆转录病毒感染的标志， 禽、鼠和人逆转录病毒如HIV。的主要重点 该项目是研究逆转录病毒的遗传变异， 这种变异对病毒感染和疾病影响。 研究 目前正在实验室进行的包括确定 逆转录病毒的点突变率;重组病毒的多态性 宿主范围逆转录病毒变异体;由于混合 逆转录病毒感染;和逆转录病毒感染的治疗 与逆转录病毒编码抗原反应的免疫毒素。 A. 报道的逆转录病毒突变率估计表明， 子代逆转录病毒在转录过程中维持几个点突变。 复制周期 相比之下，我们已经确定， 鼠逆转录病毒在单次复制过程中不维持任何点突变， 周期 研究正在进行中，以比较点突变率， 在没有选择的情况下， 为了生存能力。 B。 在小鼠中接种许多鼠逆转录病毒导致 通过重组接种的 具有内源性逆转录病毒基因的病毒。 我们已经确定了两个主要的 这些变体的抗原亚组。 这些小组似乎是 来源于不同的内源性序列， 它们的体外细胞向性。 我们目前正在构建嵌合体 两个主要亚群的病毒之间的病毒，以绘制遗传图谱 其属性的决定因素。 C. 逆转录病毒感染小鼠宿主范围变异的产生 导致混合逆转录病毒感染， 伪型 我们在感染了 莫洛尼淋巴细胞白血病病毒 此外， 似乎是一种动态现象，在不同的器官中有所不同， 在疾病过程中的变化，并可能影响传播 宿主范围变异体感染靶器官。 继续 研究将检查病毒传播的程度和细胞类型， 被宿主变异体感染 D. 蓖麻毒素A链免疫毒素的构建 与鼠逆转录病毒编码的蛋白质已经被测试的功效， 选择性地杀死受感染的细胞。 已经发现了几种免疫毒素 使用感染的体外细胞系是有效的。 初步研究使用 小鼠逆转录病毒诱导的神经退行性疾病作为治疗药物 模型表明，某些免疫毒素也具有细胞毒性， 体内感染细胞。 逆转录病毒诱导的淋巴细胞白血病， 目前正在评估作为第二种体内治疗模型。