Human immunodeficiency virus type 1 escape from RNA interference.
Sequence-specific degradation of mRNA by short interfering RNA (siRNA) allows the selective inhibition of viral proteins that are critical for human immunodeficiency virus type 1 (HIV-1) replication. The aim of this study was to characterize the potency and durability of virus-specific RNA interference (RNAi) in cell lines that stably express short hairpin RNA (shRNA) targeting the HIV-1 transactivator protein gene tat. We found that the antiviral activity of tat shRNA was abolished due to the emergence of viral quasispecies harboring a point mutation in the shRNA target region. Our results suggest that, in order for RNAi to durably suppress HIV-1 replication, it may be necessary to target highly conserved regions of the viral genome. Alternatively, similar to present antiviral drug therapy paradigms, DNA constructs expressing multiple siRNAs need to be developed that target different regions of the viral genome, thereby reducing the probability of generating escape mutants.
Boden
Daniel
D
Laboratory of Retrovirology, Division of Infectious Diseases, Department of Medicine, Brown Medical School, Providence, Rhode Island 02903, USA.
Pusch
Oliver
O
Lee
Frederick
F
Tucker
Lynne
L
Ramratnam
Bharat
B
D002460:Cell Line; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D009154:Mutation; D034622:RNA Interference; D016337:RNA, Catalytic; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism*; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D016337:RNA, Catalytic; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012367:RNA, Viral; C418481:hairpin ribozyme; D054322:tat Gene Products, Human Immunodeficiency Virus