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The HIV-1 co-receptor CCR5 has been thought a relevant target for small interfering RNA (siRNA)-based therapeutics. However, recent findings suggest that siRNA can stimulate innate cytokine responses in mammals. All siRNA agents tested were able to down-regulate the expression of CCR5, albeit with different efficiency (51–74% down-regulation), block HIV-induced syncytia formation between HIV-1 BaL-infected and uninfected CD4+ cells or block single-round HIV-1 infection as measured by a luciferase reporter assay (46–83% inhibition). Conversely, siRNA directed against CCR5 did not affect replication of a vesicular stomatitis virus (VSV) pseudotyped virus, suggesting that inhibition of HIV replication was specific to CCR5 down-regulation. However, two of four siRNA tested were able to induce the production of interleukin (IL) IL-6 (sixfold induction) and IL-8 (ninefold induction) but no interferon (IFN)-α, IFN-β, IFN-γ, tumour necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, RANTES, IL-1β, IL-10 or IL-12p70 cytokine induction was noted. In the absence of detectable IFN-α, IL-6 or IL-8 may represent markers of non-specific effects triggered by siRNA.