HIV evades RNA interference directed at TAR by an indirect compensatory mechanism.
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.
Leonard
Joshua N
JN
Department of Chemical Engineering and the Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
Shah
Priya S
PS
Burnett
John C
JC
Schaffer
David V
DV
D001483:Base Sequence; D002460:Cell Line; D006678:HIV / Q000235:genetics* / Q000502:physiology; D015658:HIV Infections / Q000628:therapy / Q000821:virology*; D016325:HIV Long Terminal Repeat; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic; D014779:Virus Replication
D034741:RNA, Small Interfering