Long lasting control of viral rebound with a new drug ABX464 targeting Rev – mediated viral RNA biogenesis

Abstract

BackgroundCurrent therapies have succeeded in controlling AIDS pandemic. However, there is a continuing need for new drugs, in particular those acting through new and as yet unexplored mechanisms of action to achieve HIV infection cure. We took advantage of the unique feature of proviral genome to require both activation and inhibition of splicing of viral transcripts to develop molecules capable of achieving long lasting effect on viral replication in humanized mouse models through inhibition of Rev-mediated viral RNA biogenesis.ResultsCurrent HIV therapies reduce viral load during treatment but titers rebound after treatment is discontinued. We devised a new drug that has a long lasting effect after viral load reduction. We demonstrate here that ABX464 compromises HIV replication of clinical isolates of different subtypes without selecting for drug resistance in PBMCs or macrophages. ABX464 alone, also efficiently compromised viral proliferation in two humanized mouse models infected with HIV that require a combination of 3TC, Raltegravir and Tenofovir (HAART) to achieve viral inhibition in current protocols. Crucially, while viral load increased dramatically just one week after stopping HAART treatment, only slight rebound was observed following treatment cessation with ABX464 and the magnitude of the rebound was maintained below to that of HAART for two months after stopping the treatment. Using a system to visualize single HIV RNA molecules in living cells, we show that ABX464 inhibits viral replication by preventing Rev-mediated export of unspliced HIV-1 transcripts to the cytoplasm and by interacting with the Cap Binding Complex (CBC). Deep sequencing of viral RNA from treated cells established that retained viral RNA is massively spliced but importantly, normal cellular splicing is unaffected by the drug. Consistently ABX464 is non-toxic in humans and therefore represents a promising complement to current HIV therapies.ConclusionsABX464 represents a novel class of anti-HIV molecules with unique properties. ABX464 has a long lasting effect in humanized mice and neutralizes the expression of HIV-1 proviral genome of infected immune cells including reservoirs and it is therefore a promising drug toward a functional cure of HIV.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0159-3) contains supplementary material, which is available to authorized users.

Randomized Trial of Food Effect on Pharmacokinetic Parameters of ABX464 Administered Orally to Healthy Male Subjects

“…This study confirmed that ABX464 is well tolerated and rapidly and substantially metabolized into ABX464 -N-glucuronide (ABX464-NGlc) in human subjects (16). Preclinical studies have also demonstrated that the ABX464-NGlc metabolite has antiviral properties in HIV-infected macrophages in vitro, which may play a role in the long-lasting antiviral effect of ABX464 after treatment termination in mouse model (11). For this reason, the PK properties of the metabolite may also be of particular therapeutic importance.…”

“…ABX464 has been demonstrated to be effective in inhibiting the replication of different HIV subtypes in peripheral blood mononuclear cells (PBMCs) and macrophages and did not induce any drug resistance for up to 24 weeks of treatment in vitro (11). ABX464 also substantially reduced virus replication in two humanized models of mice infected with HIV-1, and this was followed by a long-lasting effect on the viral load after treatment termination (11).…”

“…ABX464 also substantially reduced virus replication in two humanized models of mice infected with HIV-1, and this was followed by a long-lasting effect on the viral load after treatment termination (11). ABX464 represents the first HIV therapy able to reduce the expression of the HIV-1 proviral genome and to maintain a low viral load after treatment termination.…”

“…This inhibition is achieved by modulating the splicing of viral RNA and thereby interfering with the production of the essential regulatory proteins Rev and Tat or by inhibiting the export of viral mRNA required for Gag, Pol, and Env production and for generation of genomic RNA. ABX464 inhibits the export of unspliced viral RNA mediated by Rev, which is an essential step for virus replication, and due to this specificity does not impact normal cellular splicing (11,14,15).…”

“…None of these drugs can eliminate virus reservoirs, and all are subject to the development of drug-resistant variants. ABX464 is a first-in-class small molecule that modulates viral RNA splicing events (11). RNA splicing is an essential step required for the production of viral infectious particles.…”