A group of temperature-sensitive mutants of Moloney leukemia virus which is defective in cleavage of env precursor polypeptide in infected cells also induces hind-limb paralysis in newborn CFW/D mice

Wong, Patty; Soong, M.M.; MacLeod, Roderick; Gallick, Gary E.; Yuen, P.H.

doi:10.1016/0042-6822(83)90225-8

Cited by 62 publications

(53 citation statements)

References 13 publications

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“…MLV induce a variety of neurological deficiencies depending on the virus isolate and mouse strain (54). One common pathological feature is the induction of spongiform encephalomyelopathy in the CNS and linked deterioration of peripheral motor function (10,11,17,25,34,54); characteristic examples of this include infection of mice with CasBrE, FrCasE, or Moloney ts1 virus (7,33,56) and of rats with PVC-211, NT-40, or A8 virus (5,18,50).…”

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confidence: 99%

Disparate Regions of Envelope Protein Regulate Syncytium Formation versus Spongiform Encephalopathy in Neurological Disease Induced by Murine Leukemia Virus TR

Murphy

Honczarenko

Dugger

et al. 2004

J Virol

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The murine leukemia virus (MLV) TR1.3 provides an excellent model to study the wide range of retrovirusinduced central nervous system (CNS) pathology and disease. TR1.3 rapidly induces thrombotic events in brain microvessels and causes cell-specific syncytium formation of brain capillary endothelial cells (BCEC). A single amino acid substitution, W102G, in the MLV envelope protein (Env) regulates the pathogenic effects. The role of Env in determining this disease phenotype compared to the induction of spongiform encephalomyelitis with a longer latency, as seen in several other MLV and in human retroviruses, was determined by studying in vitro-attenuated TR1.3. Virus cloned from this selection, termed TRM, induced progressive neurological disease characterized by ataxia and paralysis and the appearance of spongiform neurodegeneration throughout the brain stem and spinal cord. This disease was associated with virus replication in both BCEC and highly ramified glial cells. TRM did not induce syncytium formation, either in vivo or in vitro. Sequence and mutational analyses demonstrated that TRM contained a reversion of Env G102W but that neurological disease mapped to the single amino acid substitution Env S159P. The results demonstrate that single nucleotide changes within disparate regions of Env control dramatically different CNS disease patterns.

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confidence: 99%

Disparate Regions of Envelope Protein Regulate Syncytium Formation versus Spongiform Encephalopathy in Neurological Disease Induced by Murine Leukemia Virus TR

Murphy

Honczarenko

Dugger

et al. 2004

J Virol

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“…Studies with chimeras constructed from the A8 virus and the non-neuropathogenic Fr-MLV clone 57 (10) identified the env gene of A8 as a primary determinant for the induction of spongiform neurodegeneration in the brains of infected rats (15). Several MLVs induce spongiform neurodegeneration when infected into neonatal mice and/or rats (1,2,4,6,17,19,20). One common feature of these viruses is that the primary determinant for the induction of neurodegenerative disease in the central nervous system (CNS) is the env gene.…”

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confidence: 99%

A Viral Non‐Coding Region Determining Neuropathogenicity of Murine Leukemia Virus A8 Is Responsible for Envelope Protein Expression in the Rat Brain

Takase‐Yoden

Wada

Watanabe

2006

Microbiology and Immunology

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A neuropathogenic variant of the Friend murine leukemia virus (Fr-MLV), clone A8, induces spongiform neurodegeneration without inflammatory infiltrates when infected into neonatal rats (15). Studies with chimeras constructed from the A8 virus and the non-neuropathogenic Fr-MLV clone 57 (10) identified the env gene of A8 as a primary determinant for the induction of spongiform neurodegeneration in the brains of infected rats (15). Several MLVs induce spongiform neurodegeneration when infected into neonatal mice and/or rats (1,2,4,6,17,19,20). One common feature of these viruses is that the primary determinant for the induction of neurodegenerative disease in the central nervous system (CNS) is the env gene. Some uninfected neurons exhibit cytopathogenicity in the brains of rats infected with neuropathogenic viruses, indicating an indirect mechanism for MLV-induced neuropathogenicity (11,18). It has been suggested that the uncleaved Env precursor protein, or Env protein with differential processing of N-linked sugar, is correlated with retrovirus-induced spongiform neurodegeneration (3,7,8,13,14). However, the pathomechanism of spongiosis induced by Env is still not understood. We recently reported that a 0.3-kb fragment containing the R-U5-5' leader sequence of A8 is necessary for neuropathogenicity in addition to the env gene (16). The 0.3-kb fragment seems to influence Env protein expression in cultured cells. Immunohistochemical studies of infected rat brains support this view, but quantitative and qualitative analysis of Env protein expressed in the brain has not been carried out yet. In this study, we detected the Env protein in rat brains infected with neuropathogenic and non-neuropathogenic viruses by Western blot. We also evaluated processing of the Env protein and its expression level by comparing it with Gag. Furthermore, we compared the ratios of Env/Gag expression between infected brains and spleens.R7f and Rec5, chimeras of neuropathogenic A8 and non-neuropathogenic 57 viruses, were inoculated into newborn Lewis rats intraperitoneally and/or intracerebrally, as described previously (15, 16). The animals were kept according to the guidelines determined by the committee at our university. Genomic DNA was isolated from the brains and spleens of rats infected with R7f and Rec5 using QIAGEN Genomic-tips (QIAGEN) according to the manufacturer's instructions. PCR to detect viral DNA was performed as described previously A Viral Non-Coding Region Determining Neuropathogenicity of Murine Leukemia Virus A8 Is Responsible for Envelope Protein Expression in the Rat BrainSayaka Takase-Yoden*, Misaho Wada, and Rihito Watanabe Department of Bioinformatics, Faculty of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan Received August 15, 2005; in revised form, October 26, 2005. Accepted December 6, 2005 Abstract: Friend murine leukemia virus clone A8 causes spongiform neurodegeneration in the rat brain. A 0.3-kb fragment containing the R-U5-5' leader sequence of A8 is required in addition to the A8-env ...

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“…ts1 is a leaky mutant because elevated temperatures do not totally inactivate the virus. Elevated temperatures only cripple the virus, since virions with decreased amounts of gp70 are released from infected cells at the restrictive temperature (44). After temperature upshift, the defective Env protein of ts1 appears to be ineffective in establishing superinfection immunity.…”

Section: Discussionmentioning

confidence: 99%

“…As a result, there is an elevated steady-state level of misfolded gPr80 env in the rough endoplasmic reticulum (39), and gp70-deficient virions are released from infected cells (44). Infection is initiated by attachment of the viral Env protein (45) to the host cell receptor protein MCAT-1 (1,35).…”

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confidence: 99%

Synthesis of Virus-Specific High-Mobility DNA after Temperature Upshift of SC-1 Cells Chronically Infected with Moloney Murine Leukemia Virus Mutant ts 1

Szurek

Brooks

2000

J Virol

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Premature termination products of reverse transcription that consist physically of viral minus-sense singlestranded DNA that is shorter than one long terminal repeat and partial DNA duplexes are dramatically increased in the central nervous system (CNS) of FVB/N mice that are infected by ts1, a temperature-sensitive mutant of Moloney murine leukemia virus. Due to their migration in agarose gels, these incomplete physical forms of DNA have been designated high-mobility (HM) DNA. In non-CNS tissues, the level of HM DNA is either low or not detectable. In order to determine the conditions that are necessary for the synthesis of HM DNA in vivo, we have characterized the physical forms of HM DNA that were synthesized in vitro in chronically infected SC-1 cells after temperature upshift. At the permissive temperature of 34°C, the chronically infected SC-1 cells did not synthesize HM DNA. After temperature upshift of the cultured cells from 34 to 37°C, the chronically infected SC-1 cells developed extremely high levels of HM DNA. Following temperature downshift of the cultured cells from 37 to 34°C, a decrease in the level of HM DNA and an increase in the level of unintegrated linear proviral DNA occurred simultaneously. These results suggested that the accumulation of HM DNA both in vitro and in vivo may be the result of superinfection.ts1 is a spontaneous temperature-sensitive mutant of Moloney murine leukemia virus (MoMuLV). Temperature sensitivity results from a single Val-253Ile substitution in gPr80env is a precursor polyprotein for the envelope protein, Env. The mature Env protein consists of gp70, a surface protein, and p15E, a transmembrane protein. At the restrictive temperature, gPr80 env is inefficiently transported from the rough endoplasmic reticulum to the Golgi apparatus (38, 39). As a result, there is an elevated steady-state level of misfolded gPr80 env in the rough endoplasmic reticulum (39), and gp70-deficient virions are released from infected cells (44). Infection is initiated by attachment of the viral Env protein (45) to the host cell receptor protein 35).Previously, we showed that the tissues of the central nervous system (CNS) of moribund paralyzed FVB/N mice contained unusually high levels of persistent incomplete physical forms of proviral DNA (36, 37). Due to their migration in agarose gels, these physical forms of DNA were designated high-mobility (HM) DNA. The two major persistent physical forms of retroviral DNA that were found in infected tissues of the CNS consisted of class I HM DNA, minus-sense single-stranded DNA that was shorter than one long terminal repeat (LTR), and class II HM DNA, partial DNA duplexes (Fig. 1A). Except for that of unintegrated linear proviral DNA, form III, the functions of extrachromosomal physical forms of retroviral DNA are not clear (for a review, see reference 9). Form III is the physical form of proviral DNA that integrates into the genome of the host cell (14). In DNA-dependent protein kinase (DNA-PK)-deficient murine scid cells, abortive integration of...

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A group of temperature-sensitive mutants of Moloney leukemia virus which is defective in cleavage of env precursor polypeptide in infected cells also induces hind-limb paralysis in newborn CFW/D mice

Cited by 62 publications

References 13 publications

Disparate Regions of Envelope Protein Regulate Syncytium Formation versus Spongiform Encephalopathy in Neurological Disease Induced by Murine Leukemia Virus TR

Disparate Regions of Envelope Protein Regulate Syncytium Formation versus Spongiform Encephalopathy in Neurological Disease Induced by Murine Leukemia Virus TR

A Viral Non‐Coding Region Determining Neuropathogenicity of Murine Leukemia Virus A8 Is Responsible for Envelope Protein Expression in the Rat Brain

Synthesis of Virus-Specific High-Mobility DNA after Temperature Upshift of SC-1 Cells Chronically Infected with Moloney Murine Leukemia Virus Mutant ts 1

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