title: Long lasting control of viral rebound with a new drug ABX464 targeting Rev - mediated viral RNA biogenesis.
abstract: BACKGROUND
  Current 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.
  
  
  RESULTS
  Current 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.
  
  
  CONCLUSIONS
  ABX464 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.
authors.affiliation: ABIVAX, 1919 route de Mende, 34293, Montpellier Cedex 5, France. noelie.campos@igmm.cnrs.fr.
authors.forename: Noëlie
authors.initials: N
authors.lastname: Campos
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology Department of Internal Medicin, University of Zurich, University Hospital, Raemistrasse 100, 8091, Zurich, Switzerland. Renier.Myburgh@usz.ch.
authors.forename: Renier
authors.initials: R
authors.lastname: Myburgh
authors.affiliation: ABIVAX, 1919 route de Mende, 34293, Montpellier Cedex 5, France. aude.garcel@igmm.cnrs.fr.
authors.forename: Aude
authors.initials: A
authors.lastname: Garcel
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS UMR 5535, 1919 route de Mende, 34293, Montpellier Cedex 5, France. audrey.vautrin@igmm.cnrs.fr.
authors.forename: Audrey
authors.initials: A
authors.lastname: Vautrin
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS UMR 5535, 1919 route de Mende, 34293, Montpellier Cedex 5, France. laure.lapasset@igmm.cnrs.fr.
authors.forename: Laure
authors.initials: L
authors.lastname: Lapasset
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology Department of Internal Medicin, University of Zurich, University Hospital, Raemistrasse 100, 8091, Zurich, Switzerland. Erika.Schlaepfer@usz.ch.
authors.forename: Erika Schläpfer
authors.initials: ES
authors.lastname: Nadal
authors.affiliation: Institut Curie, CNRS UMR9187, INSERM U1196, Centre universitaire, Bâtiment 110, 15 rue Georges Clémenceau, 91405, ORSAY CEDEX, France. florence.mahuteau@curie.fr.
authors.forename: Florence
authors.initials: F
authors.lastname: Mahuteau-Betzer
authors.affiliation: ABIVAX, 1919 route de Mende, 34293, Montpellier Cedex 5, France. romain.najman@curie.fr.
authors.forename: Romain
authors.initials: R
authors.lastname: Najman
authors.affiliation: ABIVAX, 1919 route de Mende, 34293, Montpellier Cedex 5, France. Pauline.Fornarelli@curie.fr.
authors.forename: Pauline
authors.initials: P
authors.lastname: Fornarelli
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS UMR 5535, 1919 route de Mende, 34293, Montpellier Cedex 5, France. ktantale@igmm.cnrs.fr.
authors.forename: Katjana
authors.initials: K
authors.lastname: Tantale
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS UMR 5535, 1919 route de Mende, 34293, Montpellier Cedex 5, France. Eugenia.Basyuk@igmm.cnrs.fr.
authors.forename: Eugénia
authors.initials: E
authors.lastname: Basyuk
authors.affiliation: Plate-forme de Protéomique Fonctionnelle (FPP) IGF, UMR 5203 CNRS - INSERM U661- UM, 141 rue de la Cardonille (pièce 029), 34094, Montpellier CEDEX 05, France. martial.seveno@fpp.cnrs.fr.
authors.forename: Martial
authors.initials: M
authors.lastname: Séveno
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS UMR 5535, 1919 route de Mende, 34293, Montpellier Cedex 5, France. julian.venables2@newcastle.ac.uk.
authors.forename: Julian P
authors.initials: JP
authors.lastname: Venables
authors.affiliation: Université de Montpellier, UFR Pharmacie, 15 Avenue Charles Flahault, 34000, Montpellier, France. bernard.pau4@orange.fr.
authors.forename: Bernard
authors.initials: B
authors.lastname: Pau
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS UMR 5535, 1919 route de Mende, 34293, Montpellier Cedex 5, France. edouard.bertrand@igmm.cnrs.fr.
authors.forename: Edouard
authors.initials: E
authors.lastname: Bertrand
authors.affiliation: McGill AIDS Center, Lady Davis Institute - Jewish General Hospital, Montréal, QC, Canada. mark.wainberg@mcgill.ca.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology Department of Internal Medicin, University of Zurich, University Hospital, Raemistrasse 100, 8091, Zurich, Switzerland. roberto.speck@usz.ch.
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Speck
authors.affiliation: ABIVAX, 1919 route de Mende, 34293, Montpellier Cedex 5, France. Didier.Scherrer@abivax.com.
authors.forename: Didier
authors.initials: D
authors.lastname: Scherrer
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS UMR 5535, 1919 route de Mende, 34293, Montpellier Cedex 5, France. jamal.tazi@igmm.cnrs.fr.
authors.forename: Jamal
authors.initials: J
authors.lastname: Tazi
mesh_terms: D000328:Adult; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000302:isolation & purification*; D006801:Humans; D016513:Mice, SCID; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents