HDV is a unique mammalian virus, containing the only RNA species that is known to be copied by host cell enzymes. It seems highly improbable that the cellular mechanism responsible for this activity is reserved solely for use by HDV. More likely, this is a previously unrecognized and yet innate ability of mammalian cellular polymrases. As such, the study of HDV replication should lay the initial ground rules that not only will assist in the identification of other similar agents but may also open a new field of cell research.

An interesting question will be to determine the role that RNA replication has in normal cells. Simplistically, this ability could just be an artifact from the original RNA world that no longer serves any function. This view, however, is hard to sustain in light of evolutionary considerations and the likelihood that this property may be possessed by more than one mammalian RNA polymerase. In this regard, RNA-dependent RNA synthesis has been documented in certain mammalian cells (Volloch et al. 1996). What then are the possibilities:

1. An obvious candidate is in the operation of small interfering RNA (siRNA)-mediated inhibition of protein synthesis. In particular, RNA replication may be involved to amplify the small RNA fragments prepared by the dicer complex (reviewed Agrawal et al. 2003). However, while this RNA amplification does take place in cells from simpler species, there is little indication that such amplification occurs in mammalian cells. Hence, there is a need to repeatedly transfect siRNA in mammalian cells in order to maintain siRNA-mediated inhibition.

2. Regulation of protein synthesis and other cellular functions. The world of RNA-mediated regulation has been expanding steadily in recent years with the discovery of siRNA and micro RNAs. Perhaps a further mechanism exists that is dependent on RNA copying. Indeed, given the structural similarity of some micro RNAs to HDV and viroid, it is possible that an as yet undiscovered group of these RNAs are maintained by such a mechanism.

3. Perhaps the most interesting possibility of all is in the maintenance of an ancestral RNA-sequence cache such as that thought to be involved in the extra-genomic inheritance of DNA sequence information observed in arabidopsis (Lolle et al. 2005). Could a system like this be present in human cells? Indeed, this has been suggested (Pearson 2005). In particular, rare cases of children who inherit disease-causing mutations but only show mild symptoms have been documented. Is it possible that in these individuals, the DNA of some cells have reverted to a nondisease state?

There is much to do before we understand the mechanism(s) that drive HDV RNA replication. However, the future is very exciting. Thus, in spite of falling clinical relevance, HDV provides a novel window peering into a brave new world.

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