already in human clinical trials for wet adult macular degeneration, respiratory syncitial virus (SRV) infection and acute kidney failure. The potential for competition of the clinically applied siRNAs with endogenous miRNAs is a concern as is the competition among combinations of si/shRNAs. Due to the rapid emergence of resistance mutations in viruses such as HCV and HIV, the use of combinations of sh/siRNAs represents a potential mechanism for circumventing this problem. If one of the siRNAs is more eﬃciently loaded into RISC, it could compromise the eﬀectiveness of one or more of the other siRNAs. For example, our data clearly show that an eﬀective shRNA targeted against the HIV-1 rev gene, when combined with two other hairpins, no longer provides stable, long-term inhibition of HIV replication (Figure 5). This result is consistent with previous ﬁnding by Nishitsuji et al. (35), which showed a negative eﬀect on shRNA antiviral activities when used in a combinatorial fashion. 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