Replication and Pathogenesis of RNA Viruses 
tween HDV RNA and plant viroid RNAs goes 
beyond their circular RNA structure. There are 
several structural and biochemical features that 
suggest a close evolutionary relationship be- 
tween HDV and plant viroid RNAs. Both RNA 
groups contain a "ribozyme" activity, in which 
the RNA serves as an enzyme that cleaves and li- 
gates the RNA itself. Thus HDV RNA stands at a 
peculiar place in the evolutionary ladder: it may 
have been derived from a plant pathogen by re- 
combination with a gene that gave it the ability to 
infect human cells and cause diseases. Our labora- 
tory is studying the properties of this ribozyme 
activity. We have shown that HDV RNA represents 
a new class of ribozyme, which is distinct from 
any others known. 
One important difference between HDV RNA 
and plant viroid RNAs is the ability of the former 
to synthesize a protein, hepatitis delta antigen 
(HDAg), the HDV signature protein. HDAg is re- 
quired for HDV RNA synthesis. We have been 
studying this protein's properties and functions 
and have shown that it interacts with HDV RNA in 
a specific way. HDAg may be the reason the virus 
causes diseases. 
What is the role of this protein, HDAg, in HDV 
RNA synthesis? — an unusual synthesis because 
HDV RNA is so small (1,700 nucleotides) that it 
lacks capacity to provide its own synthesizing en- 
zymes. Therefore, HDV most likely borrows cel- 
lular enzymes to do the job, which is uncharac- 
teristic of RNA viruses. Most RNA viruses must 
make their own enzymes, since normal cells do 
not appear to have this type. 
HDV thus provides a new perspective from the 
small end of the RNA spectrum. Our laboratory is 
studying one of the largest RNA viruses (corona- 
virus) and the smallest (HDV), which utilize dif- 
ferent principles for viral replication. Our stud- 
ies not only offer insights into how these viruses 
cause diseases, but also into fundamental mecha- 
nisms of RNA synthesis and RNA evolution. 
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