Replication and Pathogenesis of RNA Viruses 
Michael M.-C. Lai, M.D., Ph.D. — Investigator 
Dr. Lai is also Professor of Microbiology and Neurology at the University of Southern California School of 
Medicine, Los Angeles. He obtained his M.D. degree from National Taiwan University. He studied 
retroviruses with Peter Duesberg at the University of California, Berkeley, where he obtained his Ph.D. 
degree in molecular biology and continued for postdoctoral work. 
MEDICAL history is marked by extraordinary 
successes against viral infections, but it is 
also punctuated by the continual emergence of 
new viruses. Since viruses, in general, contain 
very limited genetic information, they must rely 
on host cells for their own growth. How they 
cause diseases and how they continue to flourish 
in nature are not only interesting subjects in 
themselves but off^er a lesson in the everyday 
workings of normal cells. Our laboratory is inter- 
ested in RNA viruses, replicating entities in 
which RNA, in contrast to DNA, is the genetic 
material. We are exploring how these viruses rep- 
licate and cause diseases. 
One of those we are studying is the corona- 
virus, named for its similar appearance to the cor- 
ona of the sun. The virus causes the common cold 
in humans and a variety of gastrointestinal and 
respiratory problems in animals. It also causes 
symptoms very similar to those of multiple sclero- 
sis, thus providing a model system for studying 
this disease. The virus has an RNA genome of 
31,000 nucleotides, which is the longest known 
stable RNA. We are interested in learning how 
this unusually large RNA expresses its genes and 
maintains its genetic stability, despite an over- 
whelmingly high frequency of error in RNA syn- 
thesis. We have recently determined the com- 
plete sequence of the genome, giving us a 
glimpse of how the viral genes express 
themselves. 
The virus utilizes a novel RNA synthesis mecha- 
nism, a discontinuous process that fuses a leader 
RNA to a gene located some distance from it. This 
unusual mechanism allows the leader RNA to 
control the expression of viral genes. We have 
recently found that the synthesis of one of the 
viral surface proteins indeed can be altered by 
minor changes in the leader RNA sequences, re- 
sulting in the variation of the viral pathogenicity. 
Furthermore, this variation can be observed dur- 
ing natural viral evolution. These observations 
suggest that the enzyme catalyzing coronaviral 
RNA synthesis is unusual, which is, indeed, sug- 
gested from the sequence of the gene encoding 
the enzyme. Our laboratory is investigating this 
novel RNA synthesis mechanism. A research grant 
from the National Institutes of Health provides 
support for this part of the research program. 
Another unusual characteristic of coronavirus 
RNA has been revealed in our findings: it can un- 
dergo genetic exchange (RNA-RNA recombina- 
tion) at an extraordinarily high rate. RNA-RNA re- 
combination was previously thought to be a rare 
event in nature. We demonstrated, however, that 
it occurs readily between coronaviruses. This re- 
combination can take place almost anywhere in 
the RNA genome, both in tissue culture cells and 
during animal infections. We recently succeeded 
in establishing that with the coronavirus, recom- 
bination can occur not only between two replicat- 
ing viral RNAs but between viral RNA and a piece 
of an RNA fragment existing inside the cell, thus 
providing a model system for RNA recombination 
between viral and cellular RNAs. This type of re- 
combination is one of the mechanisms by which 
some animal viruses become pathogenic. 
We have demonstrated that a recombinant 
virus could become a predominant viral popula- 
tion under certain conditions, replacing the pa- 
rental virus by a simple natural selection process. 
Thus recombination represents a powerful evolu- 
tionary tool for RNA viruses. From the standpoint 
of viral biology, RNA recombination may be the 
genetic mechanism by which coronaviruses weed 
out defective RNA sequences generated by errors 
in RNA synthesis. Coronavirus is thus able to 
maintain an RNA genome larger than was thought 
theoretically possible. RNA recombination has 
now been demonstrated in many different vi- 
ruses, suggesting its important role in virus evo- 
lution in nature. 
This genetic phenomenon also has an impor- 
tant implication in vaccine development for dis- 
eases such as AIDS (acquired immune deficiency 
syndrome) , since genetic exchanges between vi- 
ruses may lead to genetic instability of live, atten- 
uated virus vaccines. We are continuing to study 
the RNA recombination mechanism and attempt- 
ing to use it as a genetic tool in determining how 
viruses cause diseases. 
Another virus we are studying in our laboratory 
239 
