PHOSPHOROTHIOATE OLIGONUCLEOTIDES INHIBIT THE REPLICATION OF LENTIVIRUSES AND TYPE-D RETROVIRUSES, BUT NOT THAT OF TYPE-C RETROVIRUSES

Phosphorothioate analogs of oligodeoxynucleotides at a concentration of 2 mu M protected Himalayan tahr cells from infection by caprine arthritis encephalitis virus (CAEV) and equine dermis cells from infection by equine infectious anemia virus (EIAV). The characteristics of this inhibition against these lentiviruses are similar to those previously described for the inhibition of HIV-1 in ATH8 cells [17]. Thus, the 28-mer homo-oligomer of cytidine [S-(dC)(28)] was at least as effective as three anti-sense sequences targeted to the LTR, gag, and env regions of CAEV. The effectiveness of homo-oligomers of equal length was in the order C>>A>T, and a random 28-copolymer with a composition of 2C:1G was as effective as S-(dC)(28). Shorter oligonucleotides were less effective (28>14>5 mers) for all base compositions tested. While replication of a simian type D retrovirus was inhibited by S-(dC)(28), this compound did not inhibit the cytopathogenicity of two type C retroviruses, amphotropic murine leukemia virus (MuLV), and baboon endogenous virus, when they were tested in the same cell lines used to support the replication of lentiviruses. Southern blot analysis of the high molecular weight DNA of drug-treated CAEV-infected cells showed that S-(dC)(28) was acting at or before the reverse transcription step. Our present data and the earlier finding that S-(dC),, is a potent in vitro inhibitor of the MuLV reverse transcriptase [15] suggest that S-(dC)(28) is acting very early in the replication cycle of these lentiviruses. Since MuLV reverse transcriptase is inhibited in vitro, but its replication is not blocked in permissive cells, our data suggest that the phosphorothioate oligonucleotides are preventing virus attachment.