Combination gene therapy: synergistic inhibition of human immunodeficiency virus Tat and Rev functions by a single RNA molecule.
Combination gene therapy: synergistic inhibition of human immunodeficiency virus Tat and Rev functions by a single RNA molecule.
复制标题
组合基因疗法：通过单个RNA分子协同抑制人类免疫缺陷病毒Tat和Rev功能。
作者：
J. Lisziewicz;Gang Zeng;Catherine Gratas;John N. Weinstein;Franco Lori
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.
影响因子：
21.1
作者：
W. Greco;G. Bravo;J. C. Parsons
通讯作者：
W. Greco;G. Bravo;J. C. Parsons
DOI：
10.1073/pnas.91.20.9218
发表时间：
1994-09-27
影响因子：
11.1
作者：
WALTER, AE;TURNER, DH;ZUKER, M
通讯作者：
ZUKER, M
DOI：
10.1111/j.1432-1033.1981.tb06218.x
发表时间：
1981-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
CHOU, TC;TALALAY, P
通讯作者：
TALALAY, P