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Combination Gene Therapy: Synergistic Inhibition of Human
Immunodeficiency Virus Tat and Rev Functions by a Single RNA Molecule
Lisziewicz J, Zeng G, Gratas C, Weinstein JN, Lori F.
Hum Gene Ther 2000 Apr 10;11(6):807-15
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Abstract: Current drug combinations can achieve long-term suppression of HIV replication in infected
individuals. Unfortunately, complicated dosing schedules and high toxicity make long-term
compliance with drug regimens difficult for most patients. Gene therapy may provide a permanent
solution for HIV disease by generating cells genetically resistant to virus replication. As
with the highly active antiretroviral therapies, genetic drugs must have strong antiviral
potency and the ability to prevent the emergence of escape mutants. We have constructed
antiviral genes containing unique combinations of Tat- and Rev-binding decoys. The new
antiviral molecules are chimeric TAR-RRE RNAs that are expressed only in HIV infected cells
in a Tat-regulated manner. One RNA molecule competes for both Tat and Rev binding, and thus
blocks the activation and the expression of all viral genes. The two functional Tat- and
Rev-binding domains exhibit the highest synergy at the lowest concentration. Conservative
quantitative estimates of this synergistic effect were I = 0.24 at 50% inhibition, in terms
of the Berenbaum "interaction index," indicating that the combined construct was approximately
fourfold more potent than would be predicted on the basis of additive effects. The possibility
of HIV escape from this inhibition is unlikely, because it requires simultaneous mutation of
TAR and RRE in a manner in which both Tat and Rev preserve their respective functions. TAR-RRE
combination decoys represent the first example of mathematically proven synergistic antiviral
activity between two domains of the same molecule.
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