GENETIC STRUCTURE OF MURINE RETROVIRUSES

在其复制周期中，逆转录病毒经常通过点突变或重组过程产生变体。此类变体可表现出改变其感染性和/或致病性的不同性质。该项目的主要重点是研究逆转录病毒变异体的产生及其在疾病过程中的作用。近交系小鼠具有一个密切相关的内源性逆转录病毒序列家族。在这些小鼠被逆转录病毒如亲嗜性Friend红白血病病毒（F-MuLV）或莫洛尼淋巴细胞白血病病毒（M-MuLV）感染后，接种的病毒经历与内源性逆转录病毒序列的重组以产生新的逆转录病毒。重组病毒，称为嗜多性MuLV，表现出改变的感染性宿主范围，并利用不同于嗜亲性MuLV所利用的受体的细胞表面受体。在几种小鼠白血病中，嗜亲性MuLV接种后产生的多嗜性MuLV已被证明直接参与白血病发生。尽管小鼠中有30至40个内源性序列可能与亲嗜性MuLV重组以产生多变性病毒，但它们参与重组过程不是随机的。我们已经发现，不同的亲嗜性病毒接种一致地产生不同的多变性病毒群体。此外，我们已经发现，一个小区域的病毒基因组编码的核衣壳蛋白的基因强烈影响的内源性序列的选择，重组与嗜亲性MuLVs产生嗜多性MuLVs.Infection的逆转录病毒的主机经常在混合逆转录病毒感染的结果。混合逆转录病毒感染是由病毒的异质混合物感染或由感染后发生的遗传改变产生的。后者的主要例子是在HIV感染个体中通过点突变产生的变异体和在小鼠中通过重组产生的多变变异体。不同性质的逆转录病毒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说明了一种逐步诱导淋巴细胞白血病的机制，这种机制是由嗜亲性和多嗜性MuLV之间的病毒干扰和假型化促进的。最近，我们对混合逆转录病毒感染的研究集中在共接种嗜亲性和嗜多性MuLV混合物的小鼠上。我们已经观察到对新的重组病毒的产生、接种病毒的感染性传播和由病毒感染诱导的病理学的深刻影响。使用不同的逆转录病毒组合，我们发现在嗜亲性MuLV感染后通常观察到的新的嗜亲性MuLV的完全抑制：单独接种任一病毒后未观察到的神经系统疾病的快速诱导：嗜亲性MuLV病毒血症的严重升高，并且使用一种病毒组合，嗜亲性MuLV诱导的白血病的发作显著延迟。- 逆转录病毒，白血病，小鼠，神经病理学

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