Abstract:
Influenza A and Respiratory Syncytial Virus (RSV) are both enveloped, negative strand
RNA viruses which infect the respiratory mucosa of animals and humans. Despite
decades of research and development of antivirals and vaccines, both of these viruses
continue to be a major health concern throughout the world. The focus of my research
was to examine alternative ways of developing antiviral which would be both faster and
more effective than conventional methods of screening libraries of compounds. By
examining the nucleotide sequences of influenza A virus my colleagues and I were able
to determine conserved regions as candidates for antisense drug targets. Lead antisense
compounds were effective at inhibiting influenza A virus replication in a Balb/C mouse
model. Although resistance was observed in some strains, a combination of antisense
targeting multiple conserved regions was effective. One limitation of the antisense used
in these experiments was their inability to inhibit virus replication when administered more than 2h after infection. For RSV, I examined the potential of targeting a cellular
protein (ubiquitin) thought to interact with and be required for RSV replication. I utilized
currently available drugs to interfere with ubiquitin recycling through the proteasome.
Treatment with proteasome inhibitors reduced virus replication in cell culture and had an
indirect effect on RSV virion formation. However, treatment of RSV infection with a
proteasome inhibitor in a Balb/C mouse model resulted in an altered immune response,
increased pathology in the lungs, and increased mortality. From these results I conclude
that unless sufficient background information is available for the target of interest, the
targeted development of antivirals for influenza A and RSV is no more effective than
conventional methods.
