Molecular characterization of a neuropathogenic and nonerythroleukemogenic variant of Friend murine leukemia virus PVC-211

Masuda, Mari; Remington, Mary P.; Hoffman, Paul M.; Ruscetti, Sandra K.

doi:10.1128/jvi.66.5.2798-2806.1992

Cited by 57 publications

(37 citation statements)

References 41 publications

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“…Variant PVC-211 isolated after 30 passages of Friend virus in BALB/c mice caused a rapidly progressive hind limb paralysis when injected into newborn rats and mice and displayed an expanded tropism in tissue culture. The two mutations responsible for the altered phenotype were Glu-116 to Gly and Glu-129 to Lys in the surface protein of the virus (Kai and Furuta, 1984;Masuda et al, 1992Masuda et al, , 1996aMasuda et al, , 1996b.…”

Section: B Changes In Receptor Specificity Upon Virus Evolution In Cellmentioning

confidence: 99%

Evolution of Cell Recognition by Viruses: A Source of Biological Novelty with Medical Implications

Baranowski

Ruiz-Jarabo

Pariente

et al. 2003

Advances in Virus Research

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Receptor classCellular structure a Extracellular matrix components, sugar derivatives and lipids GalactosylceramideGangliosides Glycosaminoglycans (heparan and chondroitin sulfates) Phospholipids Sialic acid (N-acetylneuraminic acid, N-acetyl-9-O-acetylneuraminic acid and N-glycolylneuraminic acid 3-O-sulfated heparan sulfate Cell adhesion and cell-cell contact proteins -Dystroglycan Coxsackievirus-adenovirus receptor (CAR; Ig superfamily) CD4 (Ig superfamily) CEACAMs (including Bgp1a, Bgp2, and pregnancy-specific glycoprotein) Intercellular adhesion molecule type 1 (ICAM-1; Ig superfamily) Integrins Junction adhesion molecule (JAM) Laminin receptor (high affinity) MHC class I and 2 -microglobulin Neural cell adhesion molecule (NCAM) Signaling lymphocyte activation molecule

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Section: B Changes In Receptor Specificity Upon Virus Evolution In Cellmentioning

confidence: 99%

Evolution of Cell Recognition by Viruses: A Source of Biological Novelty with Medical Implications

Baranowski

Ruiz-Jarabo

Pariente

et al. 2003

Advances in Virus Research

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“…The primary difference between the enhancer motifs of A8 and 57 was found to be in the number of FVa motifs. The importance of FVa in causing the rapid progression of thymoma in rats was also ascertained by comparison of this region with the U3 sequence of PVC211, which has no tumorigenicity in rats (16,25). The LTR of PVC211 lacks two FVa sites compared with A8-LTR (Fig.…”

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Identification of Genetic Determinants That Regulate Tumorigenicity of Friend Murine Leukemia Virus in Rats

Takase‐Yoden

Watanabe

2002

Microbiology and Immunology

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Friend murine leukemia virus (FrMLV) clone A8 causes a progressive neurodegenerative disease when the virus is inoculated into newborn rats in addition to the related clones PVC211 and FB29, and of a variant, NT40, derived from FB29 (5,16,24). It has been reported that PVC211, FB29 and NT40 do not induce leukemia in rats, as they do in mice (16,17,23,25). However, clone A8 has high leukemogenic potential against both mice and rats (25). When the A8 virus was inoculated into newborn mice, all of the mice exhibited splenomegaly at 2 3 months post-infection to the same extent as FrMLV clone 57. In the case of inoculation into newborn rats, the A8 virus induced thymoma and leukemic cell infiltration to organs at 7 8 weeks postinfection, but the onset of the disease by 57-virus infection was observed at 20 weeks post-infection (25). The previous studies of chimeric viruses between A8 and 57 revealed that the ClaI-AatII fragment containing the LTR and the 5' half of the 5' leader sequence of A8 is crucial for the induction of aggressive leukemia in rats (25). The LTR of MLV contains enhancer motifs, which are important determinants of leukemogenicity, tissue tropism, and disease specificity (3, 7, 10 13). The 5' leader sequence of MLV, which extends from the 3' end of a primer-binding site to the initiation codon for gag (4, 9), also plays an important role in virus replication. This region contains a donor site for the generation of spliced subgenomic mRNA (4, 22), the packaging signal for the incorporation of genome RNA into virions (1,8), and the internal ribosomal entry mechanism that promotes the translation of gag polyprotein precursors (2). In this study, we restricted the genetic determinants responsible for the induction of thymoma and leukemic infiltration to organs with rapid progression caused by A8 virus in rats. Materials and MethodsViruses and cells. Chimeric viruses combining the high-tumorigenic A8 and the low-tumorigenic 57 (18) were prepared as described previously (24) (Fig. 2). Briefly, to construct R7a, the AatII-HindIII fragment Abstract: A neuropathogenic variant of Friend murine leukemia virus (FrMLV), clone A8, has been shown to cause thymoma and infiltration of leukemic cells to organs at 7 8 weeks post-infection in rats with a more rapid progression than clone 57. We have previously reported that the determinant for induction of aggressive leukemia in rats is located in the ClaI-AatII fragment containing the long terminal repeat (LTR) and the 5' half of the 5' leader sequence of A8 virus. Further studies of chimeric viruses restricted the determinant for the induction of thymoma to only the 0.6-kb ClaI-KpnI fragment of A8. This fragment contains a 0.1 kb region of the 3' terminus of the env gene, the intergenic region, the U3, and the 5' half of the R region in the LTR. Major differences in the fragment between A8 and 57 viruses were found in the U3 region, especially in the enhancer motifs. These results indicate that the enhancer region of A8-LTR contributes to the manifestation of thymom...

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“…Several MLV cause spongiform neurodegeneration when infected into neonatal mice or rats (1)(2)(3)(4)(5)(6)(7)(8). One common feature of these viruses, such as the neuropathogenic variant Fr-MLV A8, is that the primary determinant of the induction of neurodegenerative disease is in the env gene (9)(10)(11)(12)(13)(14)(15). The pathomechanism of spongiosis is still not well understood, but several possibilities have been proposed.…”

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confidence: 99%

Kinetic studies of the effect of a 17‐nucleotide difference in the 0.3‐kb region containing the R‐U5‐5′ leader sequence of Friend murine leukemia virus on viral gene expression

Choo

Seki

Takase‐Yoden

2013

Microbiology and Immunology

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In addition to the env gene, a 0.3-kb fragment containing the R-U5-5 0 leader sequence is essential for the induction of spongiform neurodegeneration by Friend murine leukemia virus (Fr-MLV) clone A8 and it also influences expression of the Env protein. Kinetic studies were carried out using two recombinant viruses, R7f, carrying the A8 0.3-kb fragment, and Rec5, carrying the 0.3-kb fragment of the nonneuropathogenic Fr-MLV clone 57. These analyses suggested that the 0.3-kb fragment influenced the expression level of the Env protein by regulating the amount of spliced env-mRNA rather than the amount of total viral mRNA or viral production.Key words murine leukemia virus, neuropathogenicity, R-U5-5 0 leader sequence, splicing.Several MLV cause spongiform neurodegeneration when infected into neonatal mice or rats (1-8). One common feature of these viruses, such as the neuropathogenic variant Fr-MLV A8, is that the primary determinant of the induction of neurodegenerative disease is in the env gene (9-15). The pathomechanism of spongiosis is still not well understood, but several possibilities have been proposed. For example, inefficient processing or folding of neuropathogenic Env protein may induce endoplasmic reticulum stress and/or oxidative stress (16-23). Alternatively, cellular effectors, such as cytokines and inducible nitric oxide synthase, may be aberrantly expressed in the brains of infected animals (24-31). In a previous study of the viral clone A8, we showed that a high level of expression of A8-Env protein in rat brain was correlated with neuropathogenicity (32-34). We also previously showed that, in addition to the env gene, a 0.3-kb fragment containing the R-U5-5 0 leader sequence of Fr-MLV A8 was necessary for neuropathogenicity (32). The 0.3-kb fragment influences the amount of Env protein in cultured cells and in rat brains (32,33). This fragment contains functional domains, such as a signal for poly(A) addition to mRNA that works in the 3 0 LTR, a PBS for reverse transcription, and a 5 0 splice site. However, it is not clear how the 0.3-kb fragment influences the level of Env protein. Here, we sought to answer this question by a kinetic analysis to determine the effect of the 0.3-kb fragment on viral gene expression and viral production.The chimeric virus R7f, which contains a 0.3-kb fragment of viral clone A8 and the A8-env gene on a nonneuropathogenic clone 57 background, induces spongiform neurodegeneration (Fig. 1) (32). In contrast, the chimeric virus Rec5, which contains only the A8-env gene on a clone 57 background, does not exhibit neuropathogenicity. Comparison of the sequences of the 0.3-kb fragment of clones A8 and 57 revealed that they had a 17-nucleotide difference (32).R7f and Rec5 were infected into NIH3T3 cells at a moi of 1. Western blot analysis using anti-Rauscher MLV gp70 (Quality Biotech Incorporated Resource Laboratory, NJ, USA) and anti-AKR p30Gag (Quality Biotech Incorporated Resource Laboratory) antibodies was carried out on Correspondence

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Molecular characterization of a neuropathogenic and nonerythroleukemogenic variant of Friend murine leukemia virus PVC-211

Cited by 57 publications

References 41 publications

Evolution of Cell Recognition by Viruses: A Source of Biological Novelty with Medical Implications

Evolution of Cell Recognition by Viruses: A Source of Biological Novelty with Medical Implications

Identification of Genetic Determinants That Regulate Tumorigenicity of Friend Murine Leukemia Virus in Rats

Kinetic studies of the effect of a 17‐nucleotide difference in the 0.3‐kb region containing the R‐U5‐5′ leader sequence of Friend murine leukemia virus on viral gene expression

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