GENETIC STRUCTURE OF MURINE RETROVIRUSES

鼠逆转录病毒的遗传结构

• 批准号: 6288818
• 负责人: LEONARD 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/6288818
• 关键词: gene induction /repression; laboratory mouse; murine leukemia virus; neoplasm /cancer genetics; protooncogene; viral carcinogenesis; viral leukemia; virus genetics

During their replicative cycle, retroviruses frequently generate variants through the processes of point mutation or recombination. Such variants may exhibit different properties that alter their infectivity and/or pathogenicity. The major focus of this project is the study of the generation of retrovirus variants and their role in disease processes. Inbred mouse strains harbor a family of closely related endogenous retroviral sequences. Upon infection of these mice by retroviruses such as the ecotropic Friend erythroleukemia virus (F- MuLV) or Moloney lymphocytic leukemia virus (M-MuLV), the inoculated viruses undergo recombination with the endogenous retroviral sequences to generate new retroviruses. The recombinant viruses, termed polytropic MuLVs, exhibit an altered infectious host range and utilize a cell surface receptor distinct from the receptor utilized by ecotropic MuLVs. In several murineleukemias, polytropic MuLVs generated after inoculation of ecotropic MuLVs have been shown to be directly involved in leukemogenesis. Although there are 30 to 40 endogenous sequences in mice that could potentially recombine with ecotropic MuLVs to generate polytropic viruses, their participation in the recombination process is not random. We have found that different inoculated ecotropic viruses consistently generate different populations of polytropic viruses. Furthermore, we have found that a small region of the viral genome encoding the gene for the nucleocapsid protein strongly influences the choice of endogenous sequences that recombine with the ecotropic MuLVs to generate polytropic MuLVs.Infection of the host by retroviruses frequently results in mixed retrovirus infections. Mixed retrovirus infections are generated either by infection with a heterogeneous mixture of viruses or by genetic alterations which occur subsequent to infection. Prime examples of the latter are variants which arise by point mutation in HIV-infected individuals and the polytropic variants in mice that arise by recombination. Mixed infections by retroviruses with different properties can result in virus interactions that potentially could influence their spread and pathogenicity. Our initial studies of mixed retrovirus infection illustrated a stepwise mechanism for the induction of lymphocytic leukemia facilitated by viral interference and pseudotyping between ecotropic and polytropic MuLVs. Recently our studies of mixed retrovirus infection have focused on mice co- inoculated with mixtures of ecotropic and polytropic MuLVs. We have observed profound effects on the generation of new recombinant viruses, the infectious spread of the inoculated viruses and the pathology induced by virus infection. With different retrovirus combinations we have found the complete suppression of new polytropic MuLVs normally observed after ecotropic MuLV infection: the rapid induction of a neurological disease not observed after inoculation with either virus alone: the severe elevation of polytropic MuLV viremia and, with one virus combination, a substantial delay in the onset of leukemia induced by an ecotropic MuLV. - Retroviruses, Leukemia, Mice, neuropathology

逆转录病毒在其复制周期中，经常通过点突变或重组过程产生变异。这些变异可能表现出不同的特性，从而改变其传染性和/或致病性。该项目的主要重点是研究逆转录病毒变体的产生及其在疾病过程中的作用。近亲繁殖的小鼠株含有一个密切相关的内源性逆转录病毒序列家族。当这些小鼠被逆转录病毒(如亲生态的Friend红白血病病毒（F- MuLV）或Moloney淋巴细胞白血病病毒（M-MuLV）感染后，接种的病毒与内源性逆转录病毒序列重组产生新的逆转录病毒。重组病毒，称为多嗜性mulv，表现出改变的感染宿主范围，并利用不同于生态嗜性mulv所使用的受体的细胞表面受体。在一些小鼠白血病中，接种嗜生态mulv后产生的多性mulv已被证明直接参与白血病的发生。虽然小鼠体内有30 ~ 40个内源性序列可能与生态性mulv重组产生多性病毒，但它们参与重组过程并不是随机的。我们发现不同接种的生态病毒始终产生不同的多性病毒种群。此外，我们发现病毒基因组中编码核衣壳蛋白基因的小区域强烈影响内源序列的选择，这些内源序列与生态性mulv重组以产生多性mulv。逆转录病毒对宿主的感染常常导致混合逆转录病毒感染。混合逆转录病毒感染是由异质病毒混合物感染或感染后发生的遗传改变引起的。后者的主要例子是在hiv感染个体中由点突变产生的变异和在小鼠中由重组产生的多性变异。具有不同性质的逆转录病毒的混合感染可导致病毒相互作用，从而可能影响其传播和致病性。我们对混合逆转录病毒感染的初步研究表明，在嗜生态性和多性性mulv之间，病毒干扰和假分型促进了淋巴细胞白血病的逐步诱导机制。近年来，我们对混合逆转录病毒感染的研究主要集中在共接种嗜性和多嗜性混合mulv的小鼠身上。我们已经观察到对新重组病毒的产生、接种病毒的传染传播和病毒感染引起的病理的深刻影响。在不同的逆转录病毒组合中，我们发现在生态型MuLV感染后通常观察到的新的多性MuLV完全被抑制；在单独接种任何一种病毒后未观察到的神经系统疾病的快速诱导；多性MuLV病毒血症的严重升高；在一种病毒组合中，由生态型MuLV诱导的白血病的发病明显延迟。-逆转录病毒，白血病，老鼠，神经病理学