Inhibition of replication of drug-resistant HIV type 1 isolates by polypurine tract-specific oligodeoxynucletide TFO A

A 54-base-long oligodeoxynucleotide (ODN) termed triple helix-forming oligonucleotide A (TFO A), designed against the 3'-polypurine tract (PPT) of the human immunodeficiency virus type 1 (HIV-1), exhibits longterm efficacy in antiretroviral treatment. Viral replication of strains propagated in this laboratory as well as primary patient isolates are inhibited by TFO A, whereas ODNs with a randomized sequence but identical base composition show no effect. TFO A inhibits proviral DNA synthesis. To learn more about the molecular mechanism of function of TFO A, three HIV-1 isolates whose reverse transcriptase (RT) exhibits resistance against RT inhibitors were analyzed. They exhibit resistance against azidothymidine, dideoxyinosine, deoxythiacytidine, and the nonnucleoside inhibitor nevirapine. HIV-1 replication in TFO A-treated T cell cultures was assessed by monitoring p24 viral core antigen production and syncytium formation. No p24 antigen or syncytia were detected for up to 30 days when cells that had been infected with wild-type virus received TFO A. Similarly, replication of all three mutant HIV-1 strains was completely inhibited by TFO A treatment during the whole duration of the culturing period. No viral breakthrough was detectable. These results indicate that TFO A interferes with functions of the replicative cycle distinct from polymerization by the RT.