Specific properties of shRNA-mediated CCR5 downregulation that enhance the inhibition of HIV-1 infection in combination with shRNA targeting HIV-1 rev

Treatment with RNAi against HIV-1 transcripts efficiently inhibits viral replication but induces selection of escape mutants; therefore, the CCR5 coreceptor was suggested as an additional target. Blocking viral and host transcripts improved the antiviral effect. We have used short hairpin RNA (shRNA) targeting the human CCR5 (shCCR5) or the HIV-1 rev (shRev) transcripts to demonstrate distinctive properties of anti-CCR5 shRNA: shCCR5 induced more sustained protection than shRev; partial reduction in CCR5 expression substantially decreased HIV-1 infection, and shCCR5 performed better than shRev in the mixed shRNA-treated and untreated cultures. These observations indicate that CCR5 inhibitors should be conveniently included in HIV-1 gene silencing treatment schedules when only a certain cell fraction is protected to further reduce endogenous virus in a properly ART-treated HIV-1 infected individual.

Automated summary

Treatment with RNAi against HIV-1 transcripts can effectively inhibit viral replication but also leads to the selection of escape mutants. Blocking both viral and host transcripts improves the antiviral effect. The study demonstrates that short hairpin RNA (shRNA) targeting CCR5 provides more sustained protection than shRNA targeting HIV-1 rev. Partial reduction in CCR5 expression significantly decreases HIV-1 infection, and shCCR5 performs better than shRev in mixed treated and untreated cultures.