Induction of interleukins IL‐6 and IL‐8 by siRNA
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.