A short hairpin loop-structured oligodeoxynucleotide targeting the virion-associated RNase H of HIV inhibits HIV production in cell culture and in huPBL-SCID mice.

BACKGROUND: We have recently demonstrated that an oligodeoxynucleotide (ODN) can enter HIV particles and form a local hybrid at the highly conserved polypurine tract (PPT), the target site of the ODN. This hybrid is recognized by the retrovirus-specific RNase H, which is a virion-associated enzyme. It cleaves the RNA at local hybrids and thereby destroys viral infectivity. This mechanism has been described previously in a mouse model using an oncogenic retrovirus and was commented as driving HIV into suicide. The RNase H is one of four retrovirus-specific enzymes and not yet targeted by antiviral drugs.

AIMS: We wanted to analyze the tendency of ODNs to induce mutations in cell culture and its efficacy to inhibit HIV in humanized SCID mice.

METHOD: We used cultures of CD4+ T cells infected with HIV-1 after serial passage in the presence of ODNs in the supernatant for up to 3 months, using Foscarnet as positive control, and treated HIV-infected huPBL-SCID mice repeatedly with ODN.

RESULTS: Treatment with ODN did not induce mutations of the PPT or the reverse transcriptase polymerase domain in vitro, whereas Foscarnet did. We furthermore demonstrate that ODNs inhibit HIV-1 replication in humanized HIV-infected SCID mice.