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.