GENETIC STRUCTURE OF MURINE RETROVIRUSES

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。 当这些小鼠被逆转录病毒如亲嗜性Friend鼠白血病病毒（F-MuLV）或莫洛尼淋巴细胞白血病病毒（M-MuLV）感染时，接种的病毒经历与内源性逆转录病毒基因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。 在一些情况下，多变性MuLV直接参与发病机制，包括诱导增殖性、免疫性和神经系统疾病。 逆转录病毒感染宿主后产生的变体导致混合逆转录病毒感染。这方面的主要例子是HIV感染个体中通过点突变产生的变异体和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。 该项目的主要目标是阐明混合逆转录病毒感染对疾病诱导的影响。最近，我们的混合逆转录病毒感染的研究集中在小鼠共接种嗜亲性和嗜多性MuLV的混合物。 我们已经观察到对共接种小鼠中的多变病毒的感染性传播的深远影响，伴随着非常快速的神经系统疾病的诱导，在单独接种任一病毒后未观察到。 在NFS/N小鼠与亲嗜性MuLV和多嗜性MuLV共接种后观察到初步结果，已知在IRW小鼠中而非NFS/N小鼠中具有神经致病性。这些研究已经扩展到证明NFS/N和IRW小鼠中神经系统疾病的诱导由以前未观察到的神经致病性的其他多变性病毒。 导致神经系统疾病的混合感染的常见效应是多变性病毒在中枢神经系统（CNS）外周组织中的传播大大增强。 这种现象是由嗜亲性病毒颗粒内的多嗜性病毒基因组的假型化介导的。最初在CNS中检测到的多变性MuLV也是假型的，然而随后病毒在CNS中的快速传播似乎是通过未假型化的多变性病毒体进行的。 这种快速传播几乎与神经系统症状的发作同时发生。 在混合感染中不表现出增强的外周复制的嗜多性病毒表现出较低程度的CNS感染，并且尚未观察到诱导神经系统疾病。 共接种嗜亲性和嗜多性MuLV的C57 B1/6小鼠未表现出神经系统疾病，但观察到嗜多性MuLV的外周复制增强。 与NFS/N和IRW小鼠中的发现相反，在共感染的C57 B1/6小鼠的CNS中检测到的多嗜性MuLV在整个感染过程中是假型的，并且在CNS中不表现出快速扩散。总体而言，这些研究表明，神经致病性可能是一个一般属性的多变性MuLV的外周复制的阈值是需要的CNS的入侵，和传播的多变性病毒通过相互作用的多变性受体结合蛋白与受体的CNS细胞可能是一个必要的诱导神经病理。

Inbred mouse strains harbor a family of closely related endogenous retroviral sequences. Upon infection of these mice by retroviruses such as the ecotropic Friend murine leukemia virus (F-MuLV) or Moloney lymphocytic leukemia virus (M-MuLV),the inoculated viruses undergo recombination with the endogenous retroviral genes 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 instances polytropic MuLVs have been directly implicated in pathogenesis, including the induction of proliferative, immunological, and neurological disorders. The generation of variants after infection of the host by retroviruses results in mixed retrovirus infections. Prime examples of this are variants that 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 could potentially influence their spread and pathogenicity. A primary goal of this project is to elucidate the effect of mixed retrovirus infections on the induction of disease. 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 infectious spread of the polytropic virus in co-inoculated mice, concomitant with a very rapid induction of neurological disease not observed after inoculation with either virus alone. The initial results were observed after co-inoculation of NFS/N mice with an ecotropic MuLV and a polytropic MuLV known to be neuropathogenic in IRW but not NFS/N mice. These studies have been extended to demonstrate the induction of neurological disease in NFS/N and IRW mice by other polytropic viruses that had not been previously observed to be neuropathogenic. A common effect of mixed infections resulting in neurological disease is a greatly enhanced spread of the polytropic virus in tissues peripheral to the central nervous system (CNS). This phenomenon is mediated by pseudotyping of polytropic viral genomes within ecotropic virus particles. Polytropic MuLVs initially detected in the CNS are also pseudotyped, however a subsequent rapid spread of the virus in the CNS appears to proceed by polytropic virions that are not pseudotyped. This rapid spread is nearly coincident with the onset of neurological symptoms. Polytropic viruses that do not exhibit enhanced peripheral replication in mixed infections exhibit a lesser degree of CNS infection and have not been observed to induce neurological disease. C57Bl/6 mice co-inoculated with ecotropic and polytropic MuLVs do not exhibit neurological disease, yet an enhanced peripheral replication of the polytropic MuLV is observed. In contrast to the findings in NFS/N and IRW mice, polytropic MuLVs detected in the CNS of co-infected C57Bl/6 mice are pseudotyped throughout the course of infection and do not exhibit a rapid spread in the CNS. Overall, these studies suggest that neuropathogenicity may be a general property of polytropic MuLVs; that a threshold of peripheral replication is required for invasion of the CNS, and that spread of the polytropic virus through interaction of the polytropic receptor-binding protein with receptors on CNS cells may be a requirement for the induction of neuropathology.