GENETIC STRUCTURE OF MURINE RETROVIRUSES

在复制周期中，逆转录病毒经常通过点突变或重组过程产生变异。这些变异体可能表现出不同的特性，从而改变它们的传染性和/或致病性。该项目的主要重点是研究逆转录病毒变异株的产生及其在疾病过程中的作用。近交系小鼠品系含有一组密切相关的内源性逆转录病毒序列。当这些小鼠被逆转录病毒感染时，如生态朋友红白血病病毒(F-MuLV)或莫洛尼淋巴细胞白血病病毒(M-MuLV)，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。这些重组病毒被称为多嗜性MuLV，表现出感染宿主范围的改变，并利用与生态型MuLV所利用的受体不同的细胞表面受体。在几种小鼠白血病中，接种生态型MuLV后产生的多向MuLV被证明直接参与了白血病的发生。虽然在小鼠体内有30到40个内源序列可以潜在地与生态型MuLV重组产生多嗜性病毒，但它们在重组过程中的参与并不是随机的。我们发现，不同的接种生态型病毒会持续产生不同的多嗜性病毒群。此外，我们还发现，病毒基因组中编码核衣壳蛋白基因的一小部分强烈影响内源序列的选择，内源序列与生态型MuLV重组产生多嗜性MuLV。逆转录病毒感染宿主经常导致混合逆转录病毒感染。混合逆转录病毒感染要么是由于感染了不同种类的病毒混合物，要么是由于感染后发生的基因改变。后者的主要例子是艾滋病毒感染者通过点突变产生的变异，以及小鼠通过重组产生的多变变异。不同性质的逆转录病毒的混合感染可能导致病毒相互作用，这可能会影响它们的传播和致病性。我们对混合逆转录病毒感染的初步研究表明，通过病毒干扰和生态型和多向性MuLV之间的伪分型，淋巴细胞白血病的诱导是一种逐步机制。最近，我们对混合逆转录病毒感染的研究主要集中在混合接种生态型和多效型MuLV的小鼠身上。我们观察到了对新重组病毒的产生、接种病毒的感染性传播以及病毒感染引起的病理的深刻影响。用不同的逆转录病毒组合，我们发现了在生态型MuLV感染后通常观察到的新的多向性MuLV的完全抑制：快速诱导一种单独接种后没有观察到的神经系统疾病：多嗜性MuLV病毒血症的严重升高，以及一种病毒组合，显著延迟由生态型MuLV诱导的白血病的发病。-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