Mapping of a Neurovirulence Determinant within the Envelope Protein of a Polytropic Murine Retrovirus: Induction of Central Nervous System Disease by Low Levels of Virus

Poulsen, David J.; Robertson, Shelly J.; Favara, Cynthia; Portis, John L.; Chesebro, Bruce

doi:10.1006/viro.1998.9258

Cited by 24 publications

(28 citation statements)

References 38 publications

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“…6). The high levels of virus replication in the cerebellum compared to those in other regions of the brain were in agreement with previous enzyme-linked immunosorbent assay and immunohistochemistry studies (30). Immunohistochemical analysis for virus envelope protein revealed no difference in the location or number of EC virusinfected cells in TNF-␣ Ϫ/Ϫ mice compared to those in wildtype controls (data not shown).…”

Section: Vol 78 2004 Tnf-␣ Contributes To Retroviral Neuropathogenesupporting

confidence: 91%

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Separate Sequences in a Murine Retroviral Envelope Protein Mediate Neuropathogenesis by Complementary Mechanisms with Differing Requirements for Tumor Necrosis Factor Alpha

Peterson

Hughes

Dimcheff

et al. 2004

J Virol

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The innate immune response, through the induction of proinflammatory cytokines and antiviral factors, plays an important role in protecting the host from pathogens. Several components of the innate response, including tumor necrosis factor alpha (TNF-␣), monocyte chemoattractant protein 1, interferon-inducible protein 10, and RANTES, are upregulated in the brain following neurovirulent retrovirus infection in humans and in animal models. However, it remains unclear whether this immune response is protective, pathogenic, or both. In the present study, by using TNF-␣ ؊/؊ mice we analyzed the contribution of TNF-␣ to neurological disease induced by four neurovirulent murine retroviruses, with three of these viruses encoding portions of the same neurovirulent envelope protein. Surprisingly, only one retrovirus (EC) required TNF-␣ for disease induction, and this virus induced less TNF-␣ expression in the brain than did the other retroviruses. Analysis of glial fibrillary acidic protein and F4/80 in EC-infected TNF-␣ ؊/؊ mice showed normal activation of astrocytes but not of microglia. Thus, TNF-␣-mediated microglial activation may be important in the pathogenic process initiated by EC infection. In contrast, TNF-␣ was not required for pathogenesis of the closely related BE virus and the BE virus induced disease in TNF-␣ ؊/؊ mice by a different mechanism that did not require microglial activation. These results provide new insights into the multifactorial mechanisms involved in retrovirus-induced neurodegeneration and may also have analogies to other types of neurodegeneration.

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Section: Vol 78 2004 Tnf-␣ Contributes To Retroviral Neuropathogenesupporting

confidence: 91%

“…The primary brain cell types infected by the EC virus are microglia, macrophages, and endothelia (30). In this system, infection and activation of microglia are strongly correlated with pathogenesis (28,29,33).…”

Section: Vol 78 2004 Tnf-␣ Contributes To Retroviral Neuropathogenementioning

confidence: 99%

Separate Sequences in a Murine Retroviral Envelope Protein Mediate Neuropathogenesis by Complementary Mechanisms with Differing Requirements for Tumor Necrosis Factor Alpha

Peterson

Hughes

Dimcheff

et al. 2004

J Virol

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“…Previous studies identified two residues at positions 165 and 168 in the EcoRI-ClaI region of the Fr98 envelope that contributed to neurovirulence (17). In the present study, we identified seven virulent residues in the BbsI-EcoRI region of the Fr98 envelope (Fig.…”

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confidence: 69%

“…Newborn inbred Rocky Mountain White (IRW) mice injected with BE by intraperitoneal inoculation developed clinical signs of ataxia and/or seizures at 20 to 50 days postinoculation (Fig. 1A), similar to that of mice injected with SE (17). Thus, the neurovirulent determinants of SE were encoded within the BE region of the envelope gene.…”

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confidence: 83%

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Neurovirulence of Polytropic Murine Retrovirus Is Influenced by Two Separate Regions on Opposite Sides of the Envelope Protein Receptor Binding Domain

Peterson

Pourciau

et al. 2008

J Virol

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Changes in the envelope proteins of retroviruses can alter the ability of these viruses to infect the central nervous system (CNS) and induce neurological disease. In the present study, nine envelope residues were found to influence neurovirulence of the Friend murine polytropic retrovirus Fr98. When projected on a threedimensional model, these residues were clustered in two spatially separated groups, one in variable region B of the receptor binding site and the other on the opposite side of the envelope. Further studies indicated a role for these residues in virus replication in the CNS, although the residues did not affect viral entry.Amino acid sequence variations in retroviral envelope proteins play a critical role in altering viral pathogenesis and the host response. Human immunodeficiency virus envelope variants vary in chemokine induction in vitro and may influence neurovirulence in vivo (4,18,19). Similarly, simian immunodeficiency virus, feline immunodeficiency virus, and murine retrovirus envelopes play a role in regulating virus infection, host response, and neurological disease (1,3,8,11,15). Determining which amino acid residues are required for neurovirulence may provide important information on how retroviruses induce damage in the central nervous system (CNS).The neurovirulence of the polytropic murine retrovirus Fr98 is encoded within the SphI-ClaI restriction sites of the viral genome, which contain the 3Ј end of the polymerase and most of the viral envelope gene (16). The polytropic Fr54, which differs from Fr98 by multiple nucleotide substitutions in the SphI-ClaI region, does not induce neurovirulence, despite neuroinvasion and infection of similar brain cell types (16). Two separate areas of the SphI-ClaI region influence neurovirulence, one region within the SphI-EcoRI (SE) restriction sites and one within the EcoRI-ClaI (EC) restriction sites (6). These regions mediate pathogenesis by separate mechanisms, as viruses encoding only the SE or EC region of the Fr98 genome induce disease more slowly than Fr98 does (6).Previous studies mapped the residues in the EC region responsible for neurovirulence to two residues at positions 165 and 168 (17) in the receptor binding domain (RBD) (5). However, the Fr98 residues in the SE region which are associated with neurovirulence have not been identified. In the present study, we analyzed which amino acids encoded by the SE fragment of the Fr98 envelope gene were necessary or sufficient for the induction of neurological disease.A common restriction site, BbsI, found in the 5Ј end of the envelope gene for both Fr54 and SE was used to generate a chimeric virus, BE, that coded for Fr98 residues in the envelope region, but not in the polymerase gene. Newborn inbred Rocky Mountain White (IRW) mice injected with BE by intraperitoneal inoculation developed clinical signs of ataxia and/or seizures at 20 to 50 days postinoculation (Fig. 1A), similar to that of mice injected with SE (17). Thus, the neurovirulent determinants of SE were encoded within the BE reg...

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Increased Neurovirulence of Polytropic Mouse Retroviruses Delivered by Inoculation of Brain with Infected Neural Stem Cells

et al. 1999

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Following intraperitoneal (IP) inoculation of neonatal mice, the polytropic recombinant murine leukemia virus (MuLV), Fr98, induces a severe brain disease characterized by ataxia, seizures and death. In contrast, no apparent clinical neurological disease is seen after IP infection with Fr54, a polytropic MuLV differing from Fr98 in its envelope gene sequences. In the brain both Fr98 and Fr54 infect primarily capillary endothelial cells and microglia. However, the level of microglial infection by Fr98 is twofold higher than by Fr54, which might account for the difference in neurovirulence. In the present study, in order to test directly whether an increase in the number of microglia infected by Fr54 would be sufficient to induce clinical disease, we attempted to increase the level of Fr54 in the brain by changing the route of infection. After intraventricular inoculation with Fr54-infected neural stem cells (clone C17.2), a well-established vehicle for delivery of viruses and genes to the brain, mice became ataxic and died 4 weeks postinfection. In these mice induction of brain disease was correlated with a higher level of viral antigen in the cerebrum and an increase in the number of infected microglial cells in all brain regions examined compared with mice inoculated IP. In contrast, mice inoculated with neural stem cells infected with an ecotropic nonneurovirulent murine leukemia virus, FB29, developed no clinical disease in spite of evidence for widespread infection of microglia in brain. Since the main differences between Fr54 and FB29 are in the SU (gp70) region of the envelope gene, this region is most likely to account for the differences in induction of CNS disease seen in the current experiments.

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Mapping of a Neurovirulence Determinant within the Envelope Protein of a Polytropic Murine Retrovirus: Induction of Central Nervous System Disease by Low Levels of Virus

Cited by 24 publications

References 38 publications

Separate Sequences in a Murine Retroviral Envelope Protein Mediate Neuropathogenesis by Complementary Mechanisms with Differing Requirements for Tumor Necrosis Factor Alpha

Separate Sequences in a Murine Retroviral Envelope Protein Mediate Neuropathogenesis by Complementary Mechanisms with Differing Requirements for Tumor Necrosis Factor Alpha

Neurovirulence of Polytropic Murine Retrovirus Is Influenced by Two Separate Regions on Opposite Sides of the Envelope Protein Receptor Binding Domain

Increased Neurovirulence of Polytropic Mouse Retroviruses Delivered by Inoculation of Brain with Infected Neural Stem Cells

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