Clinical and Experimental Immunology, 147: 189-196AbstractThe 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)-a, IFN-b, IFN-g, tumour necrosis factor (TNF)-a,monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)- 1a, MIP-1b,RANTES, IL-1b, IL-10 or IL-12p70 cytokine induction was noted. In the absence of detectable IFN-a, IL-6 or IL-8 may represent markers of non-specific effects triggered by siRNA.