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

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‐

**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‐

**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

**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

gles similar to those seen in other neurodegenerative diseases [14, 15].

P gene of MV encodes accessory proteins, C and V.

the acute infection [18].

served to develop.

252 Encephalitis

**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‐ nisms of persistence and pathogenicity.

**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‐ doplasmic reticulum (ER) stress and apoptosis in PBMCs and human lung epithelial cells [30, 32]. All these molecules affected in MV-infected cells might be involved in SSPE pathogenesis. As an example, long-term administration of IFNs is one type of SSPE ther‐ apy [33]. NF-κB may be a determinant of multiple sclerosis (MS) susceptibility, a chronic demyelinating disease of the CNS in humans [34]. As glial cells appear to be vulnerable to ER stress, altered expression of the molecules involved in ER stress can perturb myeli‐ nation by oligodendrocytes [35]. Apoptotic processes have also been suggested to con‐ tribute to MS, where local tissue damage involves apoptosis of oligodendrocytes and neurons [36].

**Lipid metabolism in cells persistently infected with MV.** Most studies examining gene ex‐ pression in MV-infected cells have been performed in non-neuronal cells. Because modula‐ tion in gene expression is cell-type dependent [37], studies using neuronal cells are more informative. The molecules affected during persistent infection might be different from those in the acute infection. Two studies using neuronal cells persistently infected with MV revealed alterations in lipid metabolism, such as decreased cholesterol synthesis and im‐ paired β-oxidation, that were associated with MV persistence [38, 39]. Myelination is a com‐ plex process that requires a precise stoichiometry for gene dosage, along with protein and lipid synthesis. An alteration in lipid metabolism during persistent MV infection would af‐ fect the maintenance of myelin in the CNS.
