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1.  Measles Virus Spread between Neurons Requires Cell Contact but Not CD46 Expression, Syncytium Formation, or Extracellular Virus Production 
Journal of Virology  2000;74(4):1908-1918.
In patients with subacute sclerosing panencephalitis (SSPE), which is associated with persistent measles virus (MV) infection in the brain, little infectious virus can be recovered despite the presence of viral RNA and protein. Based on studies of brain tissue from SSPE patients and our work with MV-infected NSE-CD46+ mice, which express the measles receptor CD46 on neurons, several lines of evidence suggest that the mechanism of viral spread in the central nervous system differs from that in nonneuronal cells. To examine this alternate mechanism of viral spread, as well as the basis for the loss of normal transmission mechanisms, infection and spread of MV Edmonston was evaluated in primary CD46+ neurons from transgenic mice and differentiated human NT2 neurons. As expected, unlike that between fibroblasts, viral spread between neurons occurred in the absence of syncytium formation and with minimal extracellular virus. Electron microscopy analysis showed that viral budding did not occur from the neuronal surface, although nucleocapsids were present in the cytoplasm and aligned at the cell membrane. We observed many examples of nucleocapsids present in the neuronal processes and aligned at presynaptic neuronal membranes. Cocultures of CD46+ and CD46− neurons showed that cell contact but not CD46 expression is required for MV spread between neurons. Collectively, these results suggest that the neuronal environment prevents the normal mechanisms of MV spread between neurons at the level of viral assembly but allows an alternate, CD46-independent mechanism of viral transmission, possibly through the synapse.
PMCID: PMC111669  PMID: 10644364
2.  Neurokinin-1 enables measles virus trans-synaptic spread in neurons 
Virology  2007;362(1):235-244.
Measles virus (MV), a morbillivirus that remains a significant human pathogen, can infect the central nervous system, resulting in rare but often fatal diseases, such as subacute sclerosing panencephalitis. Previous work demonstrated that MV was transmitted trans-synaptically, and that, while a cellular receptor for the hemagglutinin (H) protein was required for MV entry, it was dispensable for subsequent cell-to-cell spread. Here, we explored what role the other envelope protein, fusion (F), played in trans-synaptic transport. We made the following observations: 1) MV-F expression in infected neurons was similar to that seen in infected fibroblasts; 2) fusion inhibitory peptide (FIP), an inhibitor of MV fusion, prevented both infection and spread in primary neurons; 3) Substance P, a neurotransmitter with the same active site as FIP, also blocked neuronal MV spread; and 4) both genetic deletion and pharmacological inhibition of the Substance P receptor, neurokinin-1 (NK-1), reduced infection of susceptible mice. Together, these data implicate a role for NK-1 in MV CNS infection and spread, perhaps serving as a MVF receptor or co-receptor on neurons.
doi:10.1016/j.virol.2007.02.033
PMCID: PMC1945128  PMID: 17434199
Measles; Fusion inhibitory peptide; Substance P; neuron; subacute sclerosing panencephalitis; central nervous system; fusion; CD46; spread; neurokinin-1
3.  Expression of defective measles virus genes in brain tissues of patients with subacute sclerosing panencephalitis. 
Journal of Virology  1986;59(2):472-478.
The persistence of measles virus in selected areas of the brains of four patients with subacute sclerosing panencephalitis (SSPE) was characterized by immunohistological and biochemical techniques. The five measles virus structural proteins were never simultaneously detectable in any of the brain sections. Nucleocapsid proteins and phosphoproteins were found in every diseased brain area, whereas hemagglutinin protein was detected in two cases, fusion protein was detected in three cases, and matrix protein was detected in only one case. Also, it could be shown that the amounts of measles virus RNA in the brains differed from patient to patient and in the different regions investigated. In all patients, plus-strand RNAs specific for these five viral genes could be detected. However, the amounts of fusion and hemagglutinin mRNAs were low compared with the amounts in lytically infected cells. The presence of particular measles virus RNAs in SSPE-infected brains did not always correlate with mRNA activity. In in vitro translations, the matrix protein was produced in only one case, and the hemagglutinin protein was produced in none. These results indicate that measles virus persistence in SSPE is correlated with different defects of several genes which probably prevent assembly of viral particles in SSPE-infected brain tissue.
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PMCID: PMC253098  PMID: 3735490
4.  Measles Viruses with Altered Envelope Protein Cytoplasmic Tails Gain Cell Fusion Competence 
Journal of Virology  1998;72(2):1224-1234.
The cytoplasmic tail of the measles virus (MV) fusion (F) protein is often altered in viruses which spread through the brain of patients suffering from subacute sclerosing panencephalitis (SSPE). We transferred the coding regions of F tails from SSPE viruses in an MV genomic cDNA. Similarly, we constructed and transferred mutated tail-encoding regions of the other viral glycoprotein hemagglutinin (H) gene. From the mutated genomic cDNAs, we achieved rescue of viruses that harbor different alterations of the F tail, deletions in the membrane-distal half of the H tail, and combinations of these mutations. Viruses with alterations in any of the tails spread rapidly through the monolayer via enhanced cell-cell fusion. Double-tail mutants had even higher fusion competence but slightly decreased infectivity. Analysis of the protein composition of released mutant viral particles indicated that the tails are necessary for accurate virus envelope assembly and suggested a direct F tail-matrix (M) protein interaction. Since even tail-altered glycoproteins colocalized with M protein in intracellular patches, additional interactions may exist. We conclude that in MV infections, including SSPE, the glycoprotein tails are involved not only in virus envelope assembly but also in the control of virus-induced cell fusion.
PMCID: PMC124600  PMID: 9445022
5.  Antibody-dependent transcriptional regulation of measles virus in persistently infected neural cells. 
Journal of Virology  1992;66(9):5534-5541.
Application of neutralizing anti-hemagglutinin antibodies to mouse neuroblastoma cells (NS20Y/MS) persistently infected with measles virus (MV) leads to a significant reduction of viral structural proteins within 6 days. While the transcriptional gradient for MV-specific mRNAs remained unaffected upon antibody treatment, the total amount of MV-specific transcripts dropped by 80% after 24 h. The expression of genomic RNA was affected similarly, with slightly slower time kinetics. Both transcription and expression of the viral structural proteins could be completely reactivated when viral antibodies were removed from the tissue culture. The same findings could be obtained in rat glioma cells persistently infected with subacute sclerosing panencephalitis virus (C6/SSPE) but not in cells of nonneural origin. The data indicate that antibody-induced antigenic modulation affects the early stages of viral transcription within a few hours after the addition of antibodies and leads to an almost complete repression of viral gene expression in cells of neural origin.
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PMCID: PMC289112  PMID: 1501288
6.  Mutant Fusion Proteins with Enhanced Fusion Activity Promote Measles Virus Spread in Human Neuronal Cells and Brains of Suckling Hamsters 
Journal of Virology  2013;87(5):2648-2659.
Subacute sclerosing panencephalitis (SSPE) is a fatal degenerative disease caused by persistent measles virus (MV) infection in the central nervous system (CNS). From the genetic study of MV isolates obtained from SSPE patients, it is thought that defects of the matrix (M) protein play a crucial role in MV pathogenicity in the CNS. In this study, we report several notable mutations in the extracellular domain of the MV fusion (F) protein, including those found in multiple SSPE strains. The F proteins with these mutations induced syncytium formation in cells lacking SLAM and nectin 4 (receptors used by wild-type MV), including human neuronal cell lines, when expressed together with the attachment protein hemagglutinin. Moreover, recombinant viruses with these mutations exhibited neurovirulence in suckling hamsters, unlike the parental wild-type MV, and the mortality correlated with their fusion activity. In contrast, the recombinant MV lacking the M protein did not induce syncytia in cells lacking SLAM and nectin 4, although it formed larger syncytia in cells with either of the receptors. Since human neuronal cells are mainly SLAM and nectin 4 negative, fusion-enhancing mutations in the extracellular domain of the F protein may greatly contribute to MV spread via cell-to-cell fusion in the CNS, regardless of defects of the M protein.
doi:10.1128/JVI.02632-12
PMCID: PMC3571373  PMID: 23255801
7.  Subacute sclerosing panencephalitis: detection of measles virus RNA in appendix lymphoid tissue before clinical signs. 
An appendix removed 15 days before onset of symptoms of subacute sclerosing panencephalitis was examined retrospectively for measles virus ribonucleic acid (RNA). Tissue sections hybridised in situ to a cloned measles virus probe of deoxyribonucleic acid specific for nucleocapsid protein showed that many cells of the lymphoid tissue contained measles virus RNA. In contrast, only a few infected lymphoid cells were detected in three out of six seropositive controls and none in three seronegative infants. A widespread chronic viral infection of the immune system, established after measles, may promote or even initiate nerve cell infection in subacute sclerosing panencephalitis.
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PMCID: PMC1341304  PMID: 3092900
8.  Clearance of Measles Virus from Persistently Infected Cells by Short Hairpin RNA▿  
Journal of Virology  2009;83(18):9423-9431.
Subacute sclerosing panencephalitis (SSPE) is a demyelinating central nervous system disease caused by a persistent measles virus (MV) infection of neurons and glial cells. There is still no specific therapy available, and in spite of an intact innate and adaptive immune response, SSPE leads inevitably to death. In order to select effective antiviral short interfering RNAs (siRNAs), we established a plasmid-based test system expressing the mRNA of DsRed2 fused with mRNA sequences of single viral genes, to which certain siRNAs were directed. siRNA sequences were expressed as short hairpin RNA (shRNA) from a lentiviral vector additionally expressing enhanced green fluorescent protein (EGFP) as an indicator. Evaluation by flow cytometry of the dual-color system (DsRed and EGFP) allowed us to find optimal shRNA sequences. Using the most active shRNA constructs, we transduced persistently infected human NT2 cells expressing virus-encoded HcRed (piNT2-HcRed) as an indicator of infection. shRNA against N, P, and L mRNAs of MV led to a reduction of the infection below detectable levels in a high percentage of transduced piNT2-HcRed cells within 1 week. The fraction of virus-negative cells in these cultures was constant over at least 3 weeks posttransduction in the presence of a fusion-inhibiting peptide (Z-Phe-Phe-Gly), preventing the cell fusion of potentially cured cells with persistently infected cells. Transduced piNT2 cells that lost HcRed did not fuse with underlying Vero/hSLAM cells, indicating that these cells do not express viral proteins any more and are “cured.” This demonstrates in tissue culture that NT2 cells persistently infected with MV can be cured by the transduction of lentiviral vectors mediating the long-lasting expression of anti-MV shRNA.
doi:10.1128/JVI.00846-09
PMCID: PMC2738273  PMID: 19587038
9.  Precipitation of measles virus proteins by immunoglobulin G fractions containing groups of oligoclonal bands isolated from sera of patients with subacute sclerosing panencephalitis. 
Infection and Immunity  1982;37(1):393-396.
Groups of oligoclonal immunoglobulin G (IgG) bands were isolated from sera of patients with subacute sclerosing panencephalitis by employing preparative isoelectric focusing. Six IgG fractions containing two to three oligoclonal bands with different isoelectric points were used to precipitate the proteins from Vero cells infected with measles virus. The results showed that all of the measles virus proteins except the M protein were precipitated by all of the IgG fractions and that the precipitation of viral proteins by the fractions containing groups of oligoclonal IgG showed slightly different patterns in some sera, whereas other sera showed no significant differences. The present study indicates that oligoclonal IgGs in subacute sclerosing panencephalitis sera are not specific to individual measles virus proteins.
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PMCID: PMC347541  PMID: 7107008
10.  Tyrosine phosphorylation of measles virus nucleocapsid protein in persistently infected neuroblastoma cells. 
Journal of Virology  1995;69(4):2480-2485.
Subacute sclerosing panencephalitis is a slowly progressing fatal human disease of the central nervous system which is a delayed sequel of measles virus (MV) infection. A typical pathological feature of this disease is the presence of viral ribonucleocapsid structures in the form of inclusion bodies and the absence of infectious virus or budding viral particles. The mechanisms governing the establishment and maintenance of a persistent MV infection in brain cells are still largely unknown. To understand the mechanisms underlying MV persistence in neuronal cells, a tissue culture model was studied. Clone NS20Y/MS of the murine neuroblastoma C1300 persistently infected with the wild-type Edmonston strain of MV secretes relatively high levels of alpha/beta interferon (IFN). As shown previously, treatment of the persistently infected cultures with anti-IFN serum converted the persistent state into a productive infection indicated by the appearance of multinucleated giant cells. In this study, we have investigated whether alpha/beta IFN produced by NS20Y/MS cells activates cellular protein tyrosine kinases which will induce tyrosine phosphorylating activity specific to virus-infected cells. We present data to show augmented protein tyrosine kinase activity in the persistently infected cells. We demonstrate that the MV N protein is phosphorylated on tyrosine in addition to serine and threonine in the persistent state but not in NS20Y cells acutely infected with MV.
PMCID: PMC188923  PMID: 7884896
11.  Immune Response-Mediated Protection of Adult but Not Neonatal Mice from Neuron-Restricted Measles Virus Infection and Central Nervous System Disease 
Journal of Virology  1999;73(3):1795-1801.
In many cases of neurological disease associated with viral infection, such as measles virus (MV)-induced subacute sclerosing panencephalitis in children, it is unclear whether the virus or the antiviral immune response within the brain is the cause of disease. MV inoculation of transgenic mice expressing the human MV receptor, CD46, exclusively in neurons resulted in neuronal infection and fatal encephalitis within 2 weeks in neonates, while mice older than 3 weeks of age were resistant to both infection and disease. At all ages, T lymphocytes infiltrated the brain in response to inoculation. To determine the role of lymphocytes in disease progression, CD46+ mice were back-crossed to T- and B-cell-deficient RAG-2 knockout mice. The lymphocyte deficiency did not affect the outcome of disease in neonates, but adult CD46+ RAG-2− mice were much more susceptible to both neuronal infection and central nervous system disease than their immunocompetent littermates. These results indicate that CD46-dependent MV infection of neurons, rather than the antiviral immune response in the brain, produces neurological disease in this model system and that immunocompetent adult mice, but not immunologically compromised or immature mice, are protected from infection.
PMCID: PMC104418  PMID: 9971756
12.  The SI Strain of Measles Virus Derived from a Patient with Subacute Sclerosing Panencephalitis Possesses Typical Genome Alterations and Unique Amino Acid Changes That Modulate Receptor Specificity and Reduce Membrane Fusion Activity ▿ ‡ 
Journal of Virology  2011;85(22):11871-11882.
Subacute sclerosing panencephalitis (SSPE) is a fatal sequela associated with measles and is caused by persistent infection of the brain with measles virus (MV). The SI strain was isolated in 1976 from a patient with SSPE and shows neurovirulence in animals. Genome nucleotide sequence analyses showed that the SI strain genome possesses typical genome alterations for SSPE-derived strains, namely, accumulated amino acid substitutions in the M protein and cytoplasmic tail truncation of the F protein. Through the establishment of an efficient reverse genetics system, a recombinant SI strain expressing a green fluorescent protein (rSI-AcGFP) was generated. The infection of various cell types with rSI-AcGFP was evaluated by fluorescence microscopy. rSI-AcGFP exhibited limited syncytium-forming activity and spread poorly in cells. Analyses using a recombinant MV possessing a chimeric genome between those of the SI strain and a wild-type MV strain indicated that the membrane-associated protein genes (M, F, and H) were responsible for the altered growth phenotype of the SI strain. Functional analyses of viral glycoproteins showed that the F protein of the SI strain exhibited reduced fusion activity because of an E300G substitution and that the H protein of the SI strain used CD46 efficiently but used the original MV receptors on immune and epithelial cells poorly because of L482F, S546G, and F555L substitutions. The data obtained in the present study provide a new platform for analyses of SSPE-derived strains as well as a clear example of an SSPE-derived strain that exhibits altered receptor specificity and limited fusion activity.
doi:10.1128/JVI.05067-11
PMCID: PMC3209319  PMID: 21917959
13.  Characterization of Measles Virus-Specific Proteins Synthesized In Vivo and In Vitro from Acutely and Persistently Infected Cells 
Journal of Virology  1979;29(3):1099-1106.
Measles virus protein synthesis has been analyzed in acutely and persistently infected cells. To assess the role of measles in subacute sclerosing panencephalitis (SSPE), measles viral proteins synthesized in vivo or in vitro were tested for reactivity with serum from a guinea pig(s) immunized with measles virus and sera from patients with SSPE. Guinea pig antimeasles virus serum immunoprecipitates the viral polypeptides of 78,000 molecular weight (glycosylated [G]), 70,000 molecular weight (phosphorylated [P]), 60,000 molecular weight (nucleocapsid [N]), and 35,000 molecular weight (matrix [M]) from cells acutely infected with measles virus as well as from chronically infected cells, but in the latter case, immunoprecipitated M protein has a reduced electrophoretic migration. Sera of SSPE patients immunoprecipitated all but the G protein in acutely infected cells and only the P and N proteins from chronically infected cells. In immunoprecipitates of viral polypeptides synthesized in a reticulocyte cell-free translation system, in response to mRNA from acutely or persistently infected cells, the 78,000-molecular-weight form of the G protein was not detected among the cell-free products of either mRNA. Guinea pig antimeasles virus serum immunoprecipitated P, N, and M polypeptides from the products of either form of mRNA, whereas SSPE serum immunoprecipitated the P and N polypeptides but not the M polypeptide. The differences in immunoreactivity of the antimeasles virus antiserum and the SSPE serum are discussed in terms of possible modifications of measles virus proteins in SSPE.
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PMCID: PMC353270  PMID: 448796
14.  Subacute sclerosing panencephalitis virus dominantly interferes with replication of wild-type measles virus in a mixed infection: implication for viral persistence. 
Journal of Virology  1992;66(4):1891-1898.
Interaction between the Edmonston or Nagahata strain of acute measles virus (MV) and the defective Biken strain of MV isolated from a patient with subacute sclerosing panencephalitis (SSPE) was examined by a cell fusion protocol. Biken-CV-1 cells nonproductively infected with Biken strain SSPE virus were fused with neomycin-resistant CV-1 cells. All the fused cells selected with the neomycin analog G418 expressed Biken viral proteins, as determined by an immunofluorescence assay. This procedure enabled the transfer of Biken viral genomes into cells previously infected with MV. In the fused cells coinfected by Biken strain SSPE virus and Edmonston or Nagahata strain MV, early MV gene expression was suppressed, as determined by immunoprecipitation with strain-specific antibodies. Maturation of Edmonston strain MV was also suppressed. When the coinfected fused cells were selected with G418, Biken viral proteins remained at a constant level for up to 7 weeks. Wild-type MV proteins gradually decreased to a barely detectable level after 4 weeks and became undetectable after 7 weeks. Immunofluorescence studies showed a steady decline in cells expressing wild-type MV proteins in the coinfected cultures. These results suggest that Biken strain SSPE virus dominantly interferes with the replication of wild-type MV. The possible mechanisms of dominant interference and the implication for evolution of a persistent MV infection are discussed.
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PMCID: PMC288976  PMID: 1548746
15.  Measles virus–specific plasma cells are prominent in subacute sclerosing panencephalitis CSF 
Neurology  2007;68(21):1815-1819.
Objective
To demonstrate the specificity of expanded CD138+ plasma cell clones recovered from the CSF of a patient with subacute sclerosing panencephalitis (SSPE) for measles virus (MV).
Methods
IgG variable region sequences of single-antibody-secreting CD138+ cells sorted from SSPE CSF were amplified by single-cell PCR and analyzed. Human IgG1 recombinant antibodies (rAbs) were produced from four expanded CD138+ clones and assayed for immunoreactivity against MV proteins.
Results
Clonal expansion was a prominent feature of the SSPE plasma cell repertoire, and each of the four rAbs assayed was specific for either the MV fusion or the MV nucleocapsid protein.
Conclusions
Expanded plasma cell clones in the CSF of patients with subacute sclerosing panencephalitis produce disease-relevant antibodies. Recombinant antibodies derived from CSF B cells could provide a tool to identify target antigens in idiopathic inflammatory disorders.
doi:10.1212/01.wnl.0000262036.56594.7c
PMCID: PMC3278989  PMID: 17515543
16.  Selective inhibition of translation of the mRNA coding for measles virus membrane protein at elevated temperatures. 
Journal of Virology  1987;61(2):472-479.
The elevation of culture temperatures of C6 cells that were persistently infected with the Lec strain of the subacute sclerosing panencephalitis (SSPE) virus (C6/SSPE) resulted in immediate selective inhibition of membrane (M) protein synthesis. This phenomenon was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of total cytoplasmic lysates and immunoprecipitation with monoclonal antibody against the M protein in short-time labeling experiments. The synthesis of various viral mRNAs in the presence of actinomycin D decreased gradually at similar rates after a shift to 39 degrees C. No specific disappearance of the mRNA coding for the M protein was observed when viral RNAs isolated from the infected cells were compared before and after a shift up by Northern blot analysis. Results of pulse-chase experiments did not show any significant difference in M protein stability between 35 and 39 degrees C. This rapid block of M protein synthesis was observed not only in Vero cells that were lytically infected with plaque-purified clones from the Lec strain, clones isolated from C6/SSPE cells and the standard Edmonston strain of measles virus but also in CV1, MA160, and HeLa cells that were lytically infected with the Edmonston strain. Poly(A)+ RNAs that were extracted from C6/SSPE cells before and after a shift to 39 degrees C produced detectable phospho, nucleocapsid, and M proteins in cell-free translation systems at 32 degrees C. Even higher incubation temperatures did not demonstrate the selective depression of M protein synthesis described above in vitro. All these data indicate that M protein synthesis of measles virus is selectively suppressed at elevated temperatures because of an inability of the translation apparatus to interact with the M protein-encoded mRNA.
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PMCID: PMC253971  PMID: 3806792
17.  Measles Virus Infection and Replication in Undifferentiated and Differentiated Human Neuronal Cells in Culture 
Journal of Virology  1998;72(6):5245-5250.
Measles virus (MV) infection of the human central nervous system (CNS) typically involves widespread infection of neurons. However, little is known about how they become infected, how defective virus arises and accumulates, or how virus spreads among the cells of the CNS. In vitro studies of viral interactions with human neuronal cells may contribute to the resolution of such issues. In mixed cultures containing differentiated human neuronal (hNT2) cells and neuroepithelial cells, immunofluorescence studies show that the neurons, unlike both their NT2 progenitors and the neuroepithelial cells, are not initially susceptible to MV infection. This is possibly due to their lack of expression of CD46, a known cell surface receptor for MV. Later in the course of infection, however, both MV proteins and genomic RNA become detectable in their processes, where they contact infected, fully permissive neuroepithelial cells. Such a mechanism of virus transfer may be involved in the initiation and spread of persistent MV infection in diseases such as subacute sclerosing panencephalitis. Furthermore, mutated defective virus may readily accumulate and spread without the need, at any stage, for viral maturation and budding.
PMCID: PMC110109  PMID: 9573298
18.  Measles virus and subacute neurological disease: an unusual presentation of measles inclusion body encephalitis. 
A 20-year-old girl developed a subacute neurological illness characterized by seizures and epilepsia partialis continua, which resulted in her death within 10 weeks of her first symptom. Although she had a history of unusual reactions to viral infections, there was no evidence of any underlying disorder resulting in immunosuppression. Histopathology demonstrated the presence of dense infection with measles virus. The unusual clinical features of this cases suggest that measles virus may be responsible for a wide spectrum of neurological disease ranging from measles inclusion body encephalitis on the one hand to subacute sclerosing panencephalitis on the other.
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PMCID: PMC1083156  PMID: 6813426
19.  Subacute sclerosing panencephalitis: measles encephalitis of temperate evolution 
Postgraduate Medical Journal  1969;45(524):401-407.
Subacute sclerosing panencephalitis is a rare disorder of late childhood and early adolescence Affected patients usually show behavioural and intellectual disturbance and involuntary movements before dying in coma after about 12 months. At some stage most have characteristic electroencephalographic abnormalities. Pathologically, changes in the brain are those of subacute encephalitis with a variable gliosis of the white matter, and sometimes intranuclear inclusion bodies in neurones and glial cells.
Recent studies in many patients have shown high levels of circulating anti-measles antibodies, measles antigen in cells in the brain, and sometimes, myxo-virus filaments in cells there. These findings suggest that SSPE may be a slow measles virus infection of the nervous system. Possible explanations for the slow evolution of the encephalitis include disordered immune mechanisms and intracellular persistence of virus in a defective phase.
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PMCID: PMC2466721  PMID: 5798690
20.  Identification of a nonproductive, cell-associated form of measles virus by its resistance to inhibition by recombinant human interferon. 
Journal of Virology  1987;61(6):1919-1926.
Subacute sclerosing panencephalitis (SSPE) is a fatal disease in children and young adults that is caused by persistent infection of the central nervous system (CNS) by a nonproductive, cell-associated form of measles virus. Using an experimental model for SSPE (LEC viral strain in newborn hamsters), we have shown previously that establishment of such CNS infections involves selective elimination from the CNS of productively infected cells by host defensive mechanisms, coupled with the selective sparing of cells carrying nonproductive viral forms. That interferon (IFN) may play a role in this process was suggested by the disappearance of productively infected cells from the CNS tissues prior to the appearance of antiviral antibodies and by the demonstration of cell-associated, IFN-resistant viral variants in the virus stocks that were used. Results of this study support these conclusions by showing that similar IFN-resistant viral variants are present in the HBS strain of SSPE-derived measles virus and that these variants, in the presence of IFN, have properties that are similar to those of naturally occurring cell-associated strains of SSPE viruses, e.g., DR, IP3, and Biken. These IFN-resistant forms of HBS virus were isolated and were shown to maintain their resistance to inhibition by IFN after cloning. However, on removal of IFN, they reverted to productive forms similar to the parental HBS virus. The potential role of such viral forms in the pathogenesis of SSPE is discussed.
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PMCID: PMC254199  PMID: 3573153
21.  Western blot analyses of measles virus antibody in normal persons and in patients with multiple sclerosis, subacute sclerosing panencephalitis, or atypical measles. 
Journal of Clinical Microbiology  1986;24(3):324-329.
A version of the Western blot was developed to detect serum antibodies against measles virus polypeptides. With this technique, a seroepidemiological survey of antibodies to the several measles virus proteins in diverse measles-related conditions was conducted. The sera were obtained from individuals with a recent or long-past history of natural measles, from persons with a history of immunization with live attenuated measles vaccine, and from patients with multiple sclerosis, subacute sclerosing panencephalitis, or atypical measles. The findings indicated that live attenuated measles vaccine elicits an antibody response qualitatively resembling that of a natural infection. In addition, multiple sclerosis patients made less antibody to the measles virus M protein than did individuals with a long-past history of natural measles. Thus, the immunological reaction of multiple sclerosis patients to measles virus is qualitatively, as well as quantitatively, different from that of normal persons. Finally, persons with subacute sclerosing panencephalitis and atypical measles mounted abnormally high antibody responses to measles virus polypeptides, in particular the P protein.
PMCID: PMC268906  PMID: 3531224
22.  Persistent Infection of BSC-1 Cells by Defective Measles Virus Derived From Subacute Sclerosing Panencephalitis 
Infection and Immunity  1974;10(6):1378-1382.
A line of cells (IP-3), persistently infected with defective measles virus, was developed from co-cultures of subacute sclerosing panencephalitis-derived brain cells with monkey kidney cells (BSC-1). The line, carried for more than 45 serial passages, produced neither infectious virus nor hemagglutinin. Cultures consistently displayed a cycling focal cytopathic pattern of infection characterized by formation of syncytia, necrosis, and plaques followed by healing. Fluorescent measles antigen was present in damaged areas only, especially in syncytia. The development of syncytia was suppressed by measles antibody. Syncytia were lysed by antibody plus rabbit complement. A variant noncytopathic subline (IP-3-Ca) was derived from the 16th passage. Infectious virus was not detected. Cells were minimally positive for hemadsorption. Fluorescent measles antigen was present in all cells. Co-cultures of IP-3-Ca cells with normal BSC-1 cells developed massive syncytia and extensive destruction. The IP-3-Ca cells multiplied in the presence of measles antibodies and were destroyed by antibodies plus complement. The possible relevance of these findings to the pathogenesis of subacute sclerosing panencephalitis is discussed.
PMCID: PMC423114  PMID: 4215764
23.  Identification of interferon-resistant subpopulations in several strains of measles virus: positive selection by growth of the virus in brain tissue. 
Journal of Virology  1990;64(4):1606-1615.
Subacute sclerosing panencephalitis (SSPE) is a chronic and usually fatal central nervous system disease caused by a persistent infection with measles virus. The pathogenic mechanisms of the disease are poorly understood, but restricted expression of viral antigens within the infected tissue appears to be involved. We have previously proposed that interferon (IFN) plays a role in the pathogenesis of SSPE by interacting with viral subpopulations that are relatively resistant to IFN-mediated inhibition. Such IFN-resistant viral subpopulations have now been identified in six independent strains of measles virus, two derived from patients with measles and four derived from patients with SSPE. By means of a replicative-plating procedure, these IFN-resistant viruses were found to be heterogeneous with respect to their growth in the presence of high levels of IFN. One viral form replicates fully, with complete destruction of the infected-cell culture, whereas the other form induces a restricted, self-limited form of cytopathic effect, similar to that seen with cell-associated strains of measles virus isolated from SSPE patients. Passage of a virus stock containing both of these viral forms through the central nervous system tissue of newborn hamsters strongly selects for the viral form associated with the self-limiting type of cytopathic effect. The presence of this form of IFN-resistant virus coupled with chronic production of IFN within the central nervous system may account for viral persistence in SSPE patients.
PMCID: PMC249296  PMID: 2319647
24.  CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells▿  
Journal of Virology  2010;84(9):4183-4193.
Measles is a highly contagious human disease caused by measles virus (MeV) and remains the leading cause of death in children, particularly in developing countries. Wild-type MeV preferentially infects lymphocytes by using signaling lymphocytic activation molecule (SLAM), whose expression is restricted to hematopoietic cells, as a receptor. MeV also infects other epithelial and neuronal cells that do not express SLAM and causes pneumonia and diarrhea and, sometimes, serious symptoms such as measles encephalitis and subacute sclerosing panencephalitis. The discrepancy between the tissue tropism of MeV and the distribution of SLAM-positive cells suggests that there are unknown receptors other than SLAM for MeV. Here we identified CD147/EMMPRIN (extracellular matrix metalloproteinase inducer), a transmembrane glycoprotein, which acts as a receptor for MeV on epithelial cells. Furthermore, we found the incorporation of cyclophilin B (CypB), a cellular ligand for CD147, in MeV virions, and showed that inhibition of CypB incorporation significantly attenuated SLAM-independent infection on epithelial cells, while it had no effect on SLAM-dependent infection. To date, MeV infection was considered to be triggered by binding of its hemagglutinin (H) protein and cellular receptors. Our present study, however, indicates that MeV infection also occurs via CD147 and virion-associated CypB, independently of MeV H. Since CD147 is expressed in a variety of cells, including epithelial and neuronal cells, this molecule possibly functions as an entry receptor for MeV in SLAM-negative cells. This is the first report among members of the Mononegavirales that CD147 is used as a virus entry receptor via incorporated CypB in the virions.
doi:10.1128/JVI.02168-09
PMCID: PMC2863760  PMID: 20147391
25.  Replication of Measles Virus: Continued Synthesis of Nucleocapsid RNA and Increased Synthesis of mRNA in the Presence of Cycloheximide 
Journal of Virology  1974;14(4):758-764.
The effect of cycloheximide on virus specific RNA synthesis in Vero cells infected with either wild-strain (Edmonston) or subacute sclerosing panencephalitis strain measles virus was investigated. At 3 days postinfection, cells treated with cycloheximide (2.6 × 10−4 M) and then exposed to [3H]uridine showed a marked increase in labeled virus-specific RNA. A major portion of this incremental labeled RNA was putative viral mRNA which sedimented at 16, 22, and 30S. Five distinct classes of polyribosomes, which were not evident in untreated cells, were found in cycloheximide-treated cells and each contained similar species of virus-specific RNA. Viral nucleocapsid RNA, 50 and 18S, was synthesized and encapsidated in the presence of cycloheximide. The latter observation is in apparent contrast to reports that cycloheximide inhibits replication of RNA of classical paramyxoviruses, and may indicate that mechanisms for replicating RNA of measles virus are different from those for replicating RNA of paramyxoviruses.
PMCID: PMC355580  PMID: 4213959

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