Abstract
HIV can rapidly evolve when placed under selective pressure, including immune surveillance or the administration of antiretroviral drugs. Typically, a variant protein allows HIV to directly evade the selective pressure. Similarly, HIV has escaped suppression by RNA interference (RNAi) directed against viral RNAs by acquiring mutations at the target region that circumvent RNAi-mediated inhibition while conserving necessary viral functions. However, when we directed RNAi against the viral TAR hairpin, which plays an indispensable role in viral transcription, resistant strains were recovered, but none carried a mutation at the target site. Instead, we isolated several strains carrying promoter mutations that indirectly compensated for the RNAi by upregulating viral transcription. Combining RNAi with the application of an antiviral drug blocked replication of such mutants. Evolutionary tuning of viral transcriptional regulation may serve as a general evasion mechanism that may be targeted to improve the efficacy of antiviral therapy.
Original language | English (US) |
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Pages (from-to) | 484-494 |
Number of pages | 11 |
Journal | Cell Host and Microbe |
Volume | 4 |
Issue number | 5 |
DOIs | |
State | Published - Nov 13 2008 |
Funding
We thank John Rossi (Beckman Research Institute of the City of Hope, Duarte, CA) for pTZU6+1 and Albert Keung, Siddharth Dey, and Randolph Ashton (Department of Chemical Engineering, U.C. Berkeley) for their assistance in data collection. This work was supported by NIH R01 GM73058 and NDSEG and a NSF Graduate Fellowship (to P.S.S.).
Keywords
- MICROBIO
ASJC Scopus subject areas
- Virology
- Parasitology
- Microbiology