The CCR5 chemokine receptor plays a crucial role in the initiation of in vivo HIV infection, acting as a critical coreceptor molecule for primary strains. Individuals with mutations in the CCR5 gene that reduce its level of expression are resistant to HIV-1 infection. Since these mutations are not associated with any known clinical condition, CCR5 may be an ideal target for anti-HIV therapy. We have designed an artificial hammerhead ribozyme, denoted RzR5-76, targeted to exon 2 of the human CCR5 mRNA. When RzR5-76 activity is induced in HEK 293 cells transfected with a CCR5 expression plasmid, the surface levels of this chemokine receptor are reduced up to 60%. The results indicate that this inhibitory effect is mainly due to the catalytic activity of the ribozyme and not to its antisense properties. These preliminary data suggest that intracellular ribozymes could be used in vivo to block HIV-1 entry into human cells.