Nuclear inclusions formed during polyomavirus and papillomavirus infection

Polyoma- and papillomaviruses are small double-stranded tumorigenic DNA viruses with genomes of 5 and 8 kbp, respectively. Replication and assembly of these two viruses follow similar strategies, and both involve ND10 bodies. The VP1 capsid protein of human polyomavirus JC is targeted to ND10 domains by VP2, VP3, and agnoprotein where they are assembled into virions (Shishido-Hara et al., 2004). A similar process occurs during papillomavirus infection where the minor capsid protein, L2, is responsible for targeting capsomeres of the major capsid protein, L1, to ND10 domains (Florin et al., 2002a). This process involves L2-induced redistribution of ND10 bodies by targeting SP100 for proteasomal degradation. At this point the cellular Daxx protein is recruited (Florin et al., 2002b). Daax has multiple functions in the nucleus including transcriptional activation and modulating Fas-mediated apoptosis [reviewed by Salomoni and Khelifi (2006)]. Its role in virus replication is at present unclear.

One characteristic of papillomavirus infections is the appearance of nuclear and cytoplasmic inclusions in cells contained within warts. The size and number of inclusions is dependent on the type of papillomavirus and the site of infection. Human papillomavirus 1 (HPV-1), for example, induces many small inclusions while HPV-4 induces one single inclusion that takes over most of the cytoplasm (Croissant et al., 1985). In vivo these structures label strongly with antiserum raised against E4 gene products which are the 17-kDa E1AE4 and 16-kDa E4 proteins (Doorbar et al., 1986; Rogel-Gaillard et al., 1993). Inclusions can be induced in certain cell types in vitro by expressing E4 gene products. HPV-1 E4 staining reveals an initial association with the intermediate filament keratin and subsequent formation of inclusion bodies in the cytoplasm and nucleus (Roberts et al., 2003; Rogel-Gaillard et al., 1993). The HPV-1 cytoplasmic inclusions retain their association with keratin and appear to induce small cages surrounding E4 protein that are interconnected by keratin filaments (Roberts et al., 2003). The E4 gene gives rise to two proteins, the 17-kDa E1AE4 which can induce cytoplasmic and nuclear inclusions whereas the 16-kDa E4 can induce inclusions solely in the cytoplasm (Rogel-Gaillard et al., 1993). Interestingly, expression of E1AE4 gene product from HPV-16 induces the complete collapse of the keratin network, but not that of the microtu-bule or actin networks (Doorbar et al., 1991). It is unclear what the role of the inclusions is in viral replication or the pathology of infection. However, HPV-1 E4 expression induces the redistribution of ND10 to the periphery of nuclear inclusions in cells in culture, and similar signals are seen in vivo (Roberts et al., 2003). The temporal and functional connection between E4 and L1 redistribution of PML is unknown.

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