Relationship between retroviral replication and RNA interference machineries.

Small interfering RNAs (siRNAs) associated with gene silencing are cellular defense mechanisms against invading viruses. The viruses fight back by suppressors or escape mechanisms. The retroviruses developed a unique escape mechanism by disguising as DNA proviruses. An evolutionary relationship between the siRNA machinery and the replication machinery of retroviruses is likely. The RNA cleavage enzymes PIWI and RNase H proteins are structurally related. This relationship can be extended from structure to function, since the retroviral reverse transcriptase (RT)/RNase H can also cause silencing of viral RNA by siRNA. Thus, both enzymes can cleave RNA‐DNA hybrids and double-stranded RNA (dsRNA) with various efficiencies shown previously and here, demonstrating that their specificities are not absolute. Other similarities may exist, for example between PAZ and the RT and between RNA-binding proteins and the viral nucleocapsid protein. Dicer has some similarities with the viral integrase, since both specifically generate dinucleotide 3′-overhanging ends. We described previously the destruction of the human immunodeficiency virus (HIV) RNA by a DNA oligonucleotide ODN (oligodeoxynucleotide). Variants of the ODN indicated high length and sequence specificities, which is reminiscent of siRNA and designated here as “siDNA.” Cleavage of the viral RNA in the presence of the ODN is caused by the retroviral RT/RNase H and cellular RNase H activities. Several siRNA-mediated antiviral defense mechanisms resemble the interferon system.