multiple shrna combinations for near-complete coverage of all hiv-1 strains多个成分组合几乎完全覆盖的hiv - 1病毒株.pdfVIP

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multiple shrna combinations for near-complete coverage of all hiv-1 strains多个成分组合几乎完全覆盖的hiv - 1病毒株.pdf

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multiple shrna combinations for near-complete coverage of all hiv-1 strains多个成分组合几乎完全覆盖的hiv - 1病毒株

Mcintyre et al. AIDS Research and Therapy 2011, 8:1 /content/8/1/1 RESEARCH Open Access Multiple shRNA combinations for near-complete coverage of all HIV-1 strains * Glen J Mcintyre , Jennifer L Groneman, Yi-Hsin Yu, Anna Tran, Tanya L Applegate Abstract Background: Combinatorial RNA interference (co-RNAi) approaches are needed to account for viral variability in treating HIV-1 with RNAi, as single short hairpin RNAs (shRNA) are rapidly rendered ineffective by resistant strains. Current work suggests that 4 simultaneously expressed shRNAs may prevent the emergence of resistant strains. Results: In this study we assembled combinations of highly-conserved shRNAs to target as many HIV-1 strains as possible. We analyzed intersecting conservations of 10 shRNAs to find combinations with 4+ matching the maximum number of strains using 1220+ HIV-1 sequences from the Los Alamos National Laboratory (LANL). We built 26 combinations of 2 to 7 shRNAs with up to 87% coverage for all known strains and 100% coverage of clade B subtypes, and characterized their intrinsic suppressive activities in transient expression assays. We found that all combinations had high combined suppressive activities, though there were also large changes in the individual activities of the component shRNAs in our multiple expression cassette configurations. Conclusion: By considering the intersecting conservations of shRNA combinations we have shown that it is possible to assemble combinations of 6 and 7 highly active, highly conserved shRNAs such that there is always at least 4 shRNAs within each combination covering all currently known variants of entire HIV-1 subtypes. By extension, it may be possible to combine several combinations for complete global coverage of HIV-1 variants. Introduction