**2. Measles and the CNS sequelae**

**Measles.** Measles is a highly contagious respiratory disease caused by MV. More than 10 million people worldwide are affected by MV each year, resulting in several hundred thou‐

© 2013 Honda et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

sand deaths [4]. Clinical symptoms of infection are fever, cough, conjunctivitis, rash, and Koplik spots. Immunosuppression for many weeks after apparent recovery is also a charac‐ teristic of MV infection. CNS involvement in measles is a common feature, although most patients do not present with clinical evidence of encephalitis. However, transient electroen‐ cephalography abnormalities are observed in approximately 50% of patients [5]. Measles can induce encephalitis in at least four different paradigms: primary measles encephalitis (PME); acute post-infectious measles encephalomyelitis (APME); measles inclusion-body en‐ cephalitis (MIBE) and SSPE. PME and MIBE are caused by an active or ongoing MV infec‐ tion, but SSPE and APME are not. APME, which occurs in approximately 0.1% of MV cases (with a lethality of approximately 20%), develops shortly after infection, but active virus is not observed in the CNS. In APME and SSPE, neuropathological demyelination has been ob‐ served to develop.

**SSPE virus strains.** The sequences of viral genomes from SSPE cases are typically not re‐ lated to current circulating wild-type viruses, but instead to those in circulation when patients developed an acute MV infection. This is confirmation that SSPE is caused by a persistent MV infection [19, 20]. Genetic analyses have also revealed that persistent MVs derived from SSPE cases (SSPE virus strains, SSPEVs) contain numerous mutations. The existence of characteristic mutations common to SSPEVs has been suggested [21, 22]. The M gene of SSPEVs appears to be particularly vulnerable to mutation, and its expression is restricted. In many SSPEVs, an A-to-G hypermutation occurs in the genome and de‐ stroys the M protein-coding frames. Although hypermutation of the M gene results in the defective expression of the M protein, replacement of the M gene did not confer a neurovirulent phenotype in hamsters [23]. Hypermutations in the M gene likely slow down the migration of the virus and thereby prolong infection. A mutated M protein in‐ teracts at low affinity, or not at all, with RNP complexes and is associated with the accu‐ mulation of nucleocapsids inside infected cells [24]. Other changes in SSPEV structural proteins have been found in the F and H proteins. The F proteins of some SSPEVs have been demonstrated to contribute to neurovirulence in animals by showing hyperfusion activity [23, 25]. The H protein also contributed to neurovirulence to some extent [23,

Pathogenesis of Encephalitis Caused by Persistent Measles Virus Infection

http://dx.doi.org/10.5772/54434

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**Modifications in MV-infected cells.** The growth of RNA viruses depends on the mRNA translation machinery of the cells. Many viruses modify the host cell machinery to favor translation of their own mRNA. During the acute phase of MV infection, the virus induces suppression of protein synthesis (designated "shut-off") in host cells and viral mRNAs are preferentially translated [27]. The phosphorylation of eukaryotic initiation factor (eIF) 2α and the binding of the N protein to eIF3-p40, which are cellular initiation factors required for cap dependent tranlation, are involved in the induction of shut-off [27, 28]. The La pro‐ tein is involved in the preferential translation of viral mRNAs [29]. All these modification are found in the acute MV infection (Figure 1A). A persistent MV infection becomes clinical‐ ly apparent many years after the acute infection. There are no apparent symptoms in the time between acute infection, and the onset of SSPE clinical symptoms; this would indicate that replication of the persistently infecting MV is in equilibrium with replication of the host cells. Some as yet unidentified modifications might be involved in disease progression dur‐ ing MV persistence (Figure 1B). These need to be investigated to understand the mecha‐

**Modulation of gene expression patterns in MV-infected cells.** Several studies examin‐ ing gene expression in MV-infected cells have been reported [30-32]. MV infection of dendritic cells up-regulates a broad array of interferon (IFN)-αs, but fails to up-regulate double-stranded RNA-dependent protein kinases [31]. MV infection of human peripheral blood mononuclear cells (PBMCs) modulates the activity of NF-κB transcription factors [30]. MV infection also induces expression of molecules involved in defense against en‐

25], although it is not required for trans-synaptic transmission [26].

**3. Host cell modifications in MV persistence**

nisms of persistence and pathogenicity.

**SSPE.** SSPE is a progressive fatal neurological disease that causes widespread demyelina‐ tion of the CNS and infection of neurons. This is followed by infection of oligodendrocytes, astrocytes and endothelial cells [6]. It takes approximately 6–8 years after an acute MV infec‐ tion for the first symptoms of SSPE to appear [7, 8]. In the early stages, affected children present with poor school performance. Motor regression is eventually seen in 100% of affect‐ ed individuals, and then the disease progresses to a vegetative state [9]. Serum and cerebro‐ spinal fluid (CSF) contain high, or very high, titers of antibodies against MV [10, 11]. Intranuclear and/or intracytoplasmic inclusion bodies are often present [12, 13]. Infiltrating mononuclear cells are first apparent in the meninges, and perivascular cuffs and infiltrates can become extensive. Some infected neurons and oligodendrocytes contain fibrillary tan‐ gles similar to those seen in other neurodegenerative diseases [14, 15].

**MV.** MV is a negative-sense, single-stranded RNA virus that belongs to the genus *Morbillivi‐ rus*, family *Paramyxoviridae*. The virus is composed of six structural proteins: nucleoprotein (N), phosphoprotein (P), matrix protein (M), fusion protein (F), hemagglutinin (H), and large protein (L). Among these structural proteins, the N, P, and L proteins are essential for viral replication and transcription. MV genomic RNA is packaged into ribonucleoprotein (RNP) complexes, consisting of the N protein and a viral RNA-dependent RNA polymerase (RdRp). The RdRp is composed of the P and L proteins, both of which are responsible for replication and transcription of the MV genome. In addition to these structural proteins, the P gene of MV encodes accessory proteins, C and V.

**MV persistence.** MV produces not only an acute lytic infection, but also an occasional per‐ sistent infection. A growing body of evidence supports the persistence of MV in the infected host. As an example, a boy who had been treated for granulomatous disease using stem cell therapy died owing to MV complications [16]. Because neither the patient nor the stem cell donor had recently been exposed to MV or been vaccinated, it is most likely that MV persist‐ ed in either the donor or the patient and was reactivated. It is possible that a MV infection can persist throughout a patient's lifetime without triggering overt disease [17]. It is also possible that reactivation of a persistent MV infection can sometimes cause SSPE long after the acute infection [18].

**SSPE virus strains.** The sequences of viral genomes from SSPE cases are typically not re‐ lated to current circulating wild-type viruses, but instead to those in circulation when patients developed an acute MV infection. This is confirmation that SSPE is caused by a persistent MV infection [19, 20]. Genetic analyses have also revealed that persistent MVs derived from SSPE cases (SSPE virus strains, SSPEVs) contain numerous mutations. The existence of characteristic mutations common to SSPEVs has been suggested [21, 22]. The M gene of SSPEVs appears to be particularly vulnerable to mutation, and its expression is restricted. In many SSPEVs, an A-to-G hypermutation occurs in the genome and de‐ stroys the M protein-coding frames. Although hypermutation of the M gene results in the defective expression of the M protein, replacement of the M gene did not confer a neurovirulent phenotype in hamsters [23]. Hypermutations in the M gene likely slow down the migration of the virus and thereby prolong infection. A mutated M protein in‐ teracts at low affinity, or not at all, with RNP complexes and is associated with the accu‐ mulation of nucleocapsids inside infected cells [24]. Other changes in SSPEV structural proteins have been found in the F and H proteins. The F proteins of some SSPEVs have been demonstrated to contribute to neurovirulence in animals by showing hyperfusion activity [23, 25]. The H protein also contributed to neurovirulence to some extent [23, 25], although it is not required for trans-synaptic transmission [26].
