MOLECULAR BIOLOGY OF THE DELTA AGENT

类病毒和类病毒病原体，尤其是病原体

The viroids and viroid-like pathogens--and particularly the agent responsible for delta hepatitis--provide examples of RNA species heavily dependent on cellular components for their life cycles, creating potential imbalances in these components and cellular pathology. Several years ago we proposed a two-domain model for the 1700-base genomic RNA of the delta agent, in which the non-coding RNA was highly conserved and contained most or all of the functional domains needed for replication. This model has received wide support, and the non-coding domain has been named the "viroid-like" domain, which is now known to contain: RNA-cleaving ribozyme activities, which we have shown to contain a common motif and to be capable of trans cleavage; a region of homology with an abundant cellular RNA (the SRP RNA); two alternative secondary structures; and at least one element of local tertiary structure. These features, together with a remarkable conservation of a region of the viroid-like domain in more than ten delta strains sequenced, strongly suggest multiple functions for this RNA domain which could include binding sites for cellular proteins. We believe that many of the functions of this small RNA region--and its ability to undergo structural variation--are related; and that control of the transition from one structure to another may also control biological function. Our specific goals are (i) to carry out detailed structure:function studies on the conserved region of the delta viroid-like RNA domain in order to explain how its structural features relate to ribozyme action and control, cellular protein binding, and functional RNA transitions. The newly discovered trans ribozyme reactions will be key to this effort; (ii) to study delta pathogenesis in order to identify the cellular com- ponents (such as RNA or proteins from the SRP particles or cellular antiviral factors) which could explain the severe symptoms sometimes found in delta hepatitis; and (iii) to study cellular components and delta RNA structure involved in delta RNA replication.