Abstract
Theiler's murine encephalomyelitis virus (TMEV) is divided into two subgroups on the basis of their different biological activities. GDVII subgroup strains produce fatal poliomyelitis in mice without virus persistence or demyelination. In contrast, TO subgroup strains induce demyelinating disease with virus persistence in the spinal cords of weanling mice. Two proteins, whose open reading frames are located in the N-terminus of the polyprotein, recently have been reported to be important for TMEV biological activities. One is leader (L) protein and is processed from the most N-terminus of the polyprotein; its function is still unknown. Although the homology of capsid proteins between DA (a representative strain of TO subgroup) and GDVII strains is over 94% at the amino acid level, that of L shows only 85%. Therefore, L is thought to be a key protein for the subgroup-specific biological activities of TMEV. Various studies have demonstrated that L plays important roles in the escape of virus from host immune defenses in the early stage of infection. The second protein is a 17–18 kDa protein, L*, which is synthesized out-of-frame with the polyprotein. Only TO subgroup strains produce L* since GDVII subgroup strains have an ACG rather than AUG at the initiation site and therefore do not synthesize L*. 'Loss and gain of function' experiments demonstrate that L* is essential for virus growth in macrophages, a target cell for TMEV persistence. L* also has been demonstrated to be necessary for TMEV persistence and demyelination. Further analysis of L and L* will help elucidate the pathomechanism(s) of TMEV-induced demyelinating disease.
Highlights
Theiler's murine encephalomyelitis virus (TMEV) belongs to the genus Cardiovirus of the family Picornaviridae and is classified into two subgroups of strains [1,2,3,4]
The present review focuses on the roles of L and L* in regulating the biological activities of TMEV
The identity of capsid proteins between DA and GDVII strains is over 94% at the amino acid (AA) level, that of L shows only 85% identity [5,6]; the low identity of the AA sequence of L between both TMEV subgroups suggests that L may contribute to the determination of the DA subgroup-specific biological activities, such as attenuated neurovirulence, viral persistence and demyelination
Summary
Theiler's murine encephalomyelitis virus (TMEV) belongs to the genus Cardiovirus of the family Picornaviridae and is classified into two subgroups of strains [1,2,3,4]. The synthesis of L* is TO subgroup-specific because this alternative initiation site is not present in GDVII subgroup strains (where the L* AUG is substituted by an ACG) (Fig. 2) [6,44] This DA subgroup-specific out-of-frame protein is thought to play an important role in characterizing the different biological activities of TMEV subgroups, especially viral persistence and demyelination. It is reported that wild type-DA (which expresses L*) induces H-2Krestricted TMEV-specific cytotoxic T cells [61], In addition, the above findings regarding L* were called into http://www.jneuroinflammation.com/content/3/1/19 question by Michiels and colleagues because the absence of the L* AUG initiation codon in a mutant DAL*-1 virus generated from a different DA infectious clone had only a weak influence on virus persistence [62]. The presence of TMEV genome in macrophages could trigger a cascade of immune system, leading to immune-mediated demyelination
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