Human papillomaviruses activate caspases to induce genome amplification
Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that exhibit tropism for epithelial cells. Approximately one-third of the 100 HPV types identified infect epithelial cells of the genital tract, and a subset are the etiological agents of cervical cancers. HPVs infect cells in the basal layer of the epithelium, which become exposed through microlesions. After infection, viral genomes are established as extrachromosomal elements in the nucleus and are maintained at 50-100 copies per cell. Epithelial differentiation triggers the productive phase of the HPV life cycle, which includes genome amplification, activation of late gene expression, and assembly of mature virions. Viruses often inactivate apoptotic pathways to ensure completion of their life cycle. This study indicates that HPV proteins activate rather than suppress caspases of the intrinsic apoptotic pathway and that this activation is necessary for the productive HPV life cycle.
Human papillomaviruses activate caspases upon epithelial differentiation to induce viral genome amplification. PNAS USA, November 28 2007
The life cycle of human papillomaviruses (HPVs) is linked to epithelial differentiation, with late viral events restricted to the uppermost stratified layers. Our studies indicated that HPV activates capases-3, -7, and -9 upon differentiation, whereas minimal activation was observed in differentiating normal keratinocytes. Activation occurred in the absence of significant levels of apoptosis, suggesting a potential role for caspases in the viral life cycle. In support of this, the addition of caspase inhibitors significantly impaired differentiation-dependent viral genome amplification. A conserved caspase cleavage motif was identified in the replication protein E1 that was targeted in vitro by both recombinant caspase-3 and caspase-7. Mutation of this site inhibited amplification of viral genomes, indicating that caspase cleavage is necessary for the productive viral life cycle. Our study demonstrates that HPV activates caspases upon differentiation to facilitate productive viral replication and represents a way by which HPV controls viral gene function in differentiating cells.
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Tags: Biology, Health, Immunology, Medicine, Microbiology, Science, Virology
Its really interesting that despite ‘activating’ the caspases, there is no apoptosis. Does it mean that the downstream cellular mechanisms get resistant to these enzymes, or that the virus elaborates other substances in addition, that deactivate the response (on the effector aspect of the host cell)?