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Nucleic Acids Research, 2003, Vol. 31, No. 22 6444-6449
© 2003 Oxford University Press

Article

Nucleotide sequence homology requirements of HIV-1-specific short hairpin RNA

Oliver Pusch, Daniel Boden, Rebecca Silbermann, Fred Lee, Lynne Tucker and Bharat Ramratnam*

Laboratory of Retrovirology, Division of Infectious Diseases, 55 Claverick Street, 4th floor, Department of Medicine, Brown Medical School, Providence, RI 02903, USA

*To whom correspondence should be addressed. Tel: +1 401 444 5219; Fax: +1 401 444 2939; Email: bramratnam{at}lifespan.org
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors

The degradation of a selected mRNA species by RNA interference requires a high degree of homology between the short interfering or short hairpin RNA (si or shRNA) and its target. Recent reports have demonstrated that the number and location of nucleotide mismatches affect the activity of si/shRNA. Here, we systematically examined the effect of single nucleotide mutations in all 21 positions of an effective shRNA that targets the gag gene of HIV-1. We found that all mutant shRNAs exerted RNAi activity but were less effective in gene silencing compared to the wild-type gag shRNA. The most pronounced reduction in function was observed with mutations in the central and 5' regions of the shRNA. Our results demonstrate that optimal gene silencing requires perfect homology between shRNA and the chosen target, but that a variable degree of silencing occurs, depending upon the precise location of nucleotide mismatches.


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