Experimental demyelination induced by coronavirus JHM (MHV-4): molecular identification of a viral determinant of paralytic disease

Fleming, John O.; Trousdale, Melvin D.; Bradbury, Janet M.; Stohlman, Stephen A.; Weiner, Leslie P.

doi:10.1016/0882-4010(87)90033-7

Cited by 71 publications

(75 citation statements)

References 30 publications

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“…By contrast, encephalomyelitis induced by infection with the closely related V-2 variant is essentially asymptomatic and is characterized by little or no demyelination (10,21). Despite these vastly different disease outcomes, infectious virus is cleared from the CNS with similar kinetics (11,21). During acute JHMV infection, CD8 ϩ T cells are the primary immune effectors responsible for eliminating infectious virus (29).…”

Section: Cd8mentioning

confidence: 99%

Role of Viral Persistence in Retaining CD8⁺T Cells within the Central Nervous System

Marten¹,

Stohlman

Bergmann

2000

J Virol

124

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The continued presence of virus-specific CD8؉ T cells within the central nervous system (CNS) following resolution of acute viral encephalomyelitis implicates organ-specific retention. The role of viral persistence in locally maintaining T cells was investigated by infecting mice with either a demyelinating, paralytic (V-1) or nonpathogenic (V-2) variant of a neurotropic mouse hepatitis virus, which differ in the ability to persist within the CNS. Class I tetramer technology revealed more infiltrating virus-specific CD8 ؉ T cells during acute V-1 compared to V-2 infection. However, both total and virus-specific CD8 ؉ T cells accumulated at similar peak levels in spinal cords by day 10 postinfection (p.i.). Decreasing viral RNA levels in both brains and spinal cords following initial virus clearance coincided with an overall progressive loss of both total and virus-specific CD8

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Section: Cd8mentioning

confidence: 99%

Role of Viral Persistence in Retaining CD8⁺T Cells within the Central Nervous System

Marten¹,

Stohlman

Bergmann

2000

J Virol

124

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“…The J.2.2v-1 neutralization mAb-derived variant of neurotropic JHMV (34,35) was injected intracerebrally in a volume of 30 l containing 500 PFU. Tissue levels of infectious virus were determined from clarified homogenates prepared from one half brain by plaque assay on monolayers of delayed brain tumor cells as previously described (20,21).…”

Section: Virus Infection and Titer Determinationmentioning

confidence: 99%

“…Clinical disease was scored as previously described (34,35). Briefly, mice were graded as follows: 0, healthy; 1, ruffled hair and hunchbacked appearance; 2, reduced mobility and inability to upright; 3, paralysis and wasting; 4, death.…”

Section: Clinical Diseasementioning

confidence: 99%

Mechanisms of Central Nervous System Viral Persistence: the Critical Role of Antibody and B Cells

Ramakrishna

Stohlman

Atkinson

et al. 2002

The Journal of Immunology

111

168

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Contributions of humoral and cellular immunity in controlling neurotropic mouse hepatitis virus persistence within the CNS were determined in B cell-deficient JHD and syngeneic H-2d B cell+ Ab-deficient mice. Virus clearance followed similar kinetics in all mice, confirming initial control of virus replication by cellular immunity. Nevertheless, virus reemerged within the CNS of all Ab-deficient mice. In contrast to diminished T cell responses in H-2b B cell-deficient μMT mice, the absence of B cells or Ab in the H-2d mice did not compromise expansion, recruitment into the CNS, or function of virus-specific CD4+ and CD8+ T cells. The lack of B cells and lymphoid architecture thus appears to manifest itself on T cell responses in a genetically biased manner. Increasing viral load did not enhance frequencies or effector function of virus-specific T cells within the CNS, indicating down-regulation of T cell responses. Although an Ab-independent antiviral function of B cells was not evident during acute infection, the presence of B cells altered CNS cellular tropism during viral recrudescence. Reemerging virus localized almost exclusively to oligodendroglia in B cell+ Ab-deficient mice, whereas it also replicated in astrocytes in B cell-deficient mice. Altered tropism coincided with distinct regulation of CNS virus-specific CD4+ T cells. These data conclusively demonstrate that the Ab component of humoral immunity is critical in preventing virus reactivation within CNS glial cells. B cells themselves may also play a subtle role in modulating pathogenesis by influencing tropism.

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“…Studies on the antigenic variants of the JHM strain of MHV suggest that E2 is important for determining the pathogenic potential of the virus (6,7). For instance, neutralization-resistant variants isolated following sequential treatment of wild-type JHM with two anti-E2 monoclonal antibodies (J.7.2 and J.2.2) have greatly reduced ability to cause either encephalitis or demyelination (8). Thus, the two antigenic sites recognized by these antibodies are important components of the neuropathogenic determinants of the virus.…”

mentioning

confidence: 99%

RNA recombination of coronaviruses: localization of neutralizing epitopes and neuropathogenic determinants on the carboxyl terminus of peplomers.

Makino¹,

Fleming²,

Keck³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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Murine coronaviruses undergo RNA recombination at a very high frequency. We have obtained a series of recombinant viruses using neutralizing monoclonal antibodies in conjunction with temperature-sensitive markers. All of the recombinants obtained have a crossover within gene C, which encodes the peplomer protein of the virus. The genetic structure of these recombinants suggests that the antigenic regions recognized by these neutralizing monoclonal antibodies are localized on the carboxyl-terminal one-third of the peplomer protein. Since the two monoclonal antibodies used are also associated with the critical determinants of virus neuropathogenicity, we conclude that both the neutralizing antibody binding sites and determinants of pathogenicity are localized at the carboxyl-terminal one-third of the peplomer. The variation of crossover sites in different recombinant viruses also allowed precise mapping of additional antigenic sites. RNA recombination thus presents a powerful genetic tool, and the carboxylterminal localization of the biological functions of peplomers suggests a distinct conformation of these viral membrane proteins.Mouse hepatitis virus (MHV), a coronavirus, is an enveloped virus containing two envelope glycoproteins, El and E2, and a nucleocapsid protein, N (1). The N protein has a molecular weight of 60,000 and is closely associated with viral RNA. The El glycoprotein has a molecular weight of -25,000 and probably serves as a matrix protein. The E2 glycoprotein, a 180-kDa heterodimer, forms the projecting spikes or peplomers on the surface of the virus particle and is involved in the attachment of virus to target cells, in the induction of cell-to-cell fusion, and in the elicitation of neutralizing antibodies (1-3). Competitive binding studies have identified at least six major antigenic sites on the E2, three of which are involved in virus neutralization (refs. 4 MHV contains a single piece of single-stranded RNA genome of positive polarity (9). The RNA contains at least seven genes, termed genes A through G in the 5'-3' order, based on the finding that, in infected cells, six subgenomic and one genomic mRNAs are expressed (10). These mRNAs have a 3'-coterminal, nested-set structure, i.e., the sequence of each mRNA is contained entirely within the next larger mRNA (10). Only the 5'-specific portions, which do not overlap with the next smaller mRNAs, are translated. Furthermore, each mRNA contains a leader sequence of '70 nucleotides, which is derived from the 5' end of the genome and joined to the mRNAs by a mechanism of "leader-primed transcription" (11,12). Despite the fact that MHV genome is a single, nonsegmented RNA, our laboratory has demonstrated that MHV can undergo RNA-RNA recombination at an extremely high frequency (13), reminiscent of the genetic reassortment of viruses with segmented RNA genomes. This observation suggests that fragmented RNA intermediates might be generated during replication of MHV RNA, probably by a mechanism of discontinuous and nonprocessive RNA synth...

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Experimental demyelination induced by coronavirus JHM (MHV-4): molecular identification of a viral determinant of paralytic disease

Cited by 71 publications

References 30 publications

Role of Viral Persistence in Retaining CD8⁺T Cells within the Central Nervous System

Role of Viral Persistence in Retaining CD8⁺T Cells within the Central Nervous System

Mechanisms of Central Nervous System Viral Persistence: the Critical Role of Antibody and B Cells

RNA recombination of coronaviruses: localization of neutralizing epitopes and neuropathogenic determinants on the carboxyl terminus of peplomers.

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Experimental demyelination induced by coronavirus JHM (MHV-4): molecular identification of a viral determinant of paralytic disease

Cited by 71 publications

References 30 publications

Role of Viral Persistence in Retaining CD8+T Cells within the Central Nervous System

Role of Viral Persistence in Retaining CD8+T Cells within the Central Nervous System

Mechanisms of Central Nervous System Viral Persistence: the Critical Role of Antibody and B Cells

RNA recombination of coronaviruses: localization of neutralizing epitopes and neuropathogenic determinants on the carboxyl terminus of peplomers.

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Product

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Role of Viral Persistence in Retaining CD8⁺T Cells within the Central Nervous System

Role of Viral Persistence in Retaining CD8⁺T Cells within the Central Nervous System