CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

Conclusions : In this non comparative proof of concept trial, most patients with CT< 20 had severe kidney failure and died, with no indication that favipiravir monotherapy improved survival. Patients with CT>20 had a lower mortality rate compared to pre-trial figures in the same settings. These preliminary data encourage continued testing of favipiravir with particular attention to identifying patients earlier in disease course, and to explore other therapeutic options, including combinations, in patients who present at advanced stages. Session O-9 Oral Abstracts Room 6D 10:00 am– 12:15 pm

New Insights Into HIV Persistence, Latency Reversal, and Viremia Rebound 104LB Durable Control of Viral Rebound in Humanized Mice by ABX464 Targeting Rev Functions

Noelie Campos 1 ; Renier Myburgh 3 ; Aude Garcel 1 ; AudreyVautrin 2 ; Laure Lapasset 2 ; KatjanaTantale 2 ; MarkWainberg 4 ; Roberto Speck 3 ; Didier Scherrer 1 ; Jamal Tazi 2 1 ABIVAX, Montpellier, France; 2 University of Montpellier, Montpellier, France; 3 University of Zurich, Zurich, Switzerland; 4 McGill AIDS Center, Montréal, Canada

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 through inhibition of rev-mediated viral RNA biogenesis Methods: A dedicated library was designed and synthesized to modulate HIV RNA splicing ( WO2012080953, June 2012) . The library was screened on infected PBMCs from healthy donors and ABX464 was selected. Deep sequencing of viral RNA from treated cells established that ABX464 does not select for mutations, however, induced massive splicing of viral RNA. Using a system to visualize single HIV RNA molecules in living cells, we established that ABX464 interferes with Rev-mediated RNA biogenesis. Two humanized mouse models were used to test the efficacy of ABX464 in vivo; SCID mice reconstituted with PBMCs and newborn NOG mice transplanted with CD34+ haematopoietic progenitor cells isolated from umbilical cord blood. Results: ABX464 compromises HIV replication of clinical isolates of different subtypes without selecting for drug resistance in PBMCs or macrophages. ABX464 inhibits viral replication by preventing Rev-mediated export of unspliced HIV-1 transcripts to the cytoplasm. Retained viral RNA is massively spliced but normal cellular splicing is unaffected by the drug. ABX464 alone, also efficiently compromised viral proliferation in two humanized mouse models infected with HIV that require a combination of 3TC, Raltegravir and tenofovir (ART) to achieve viral inhibition in current protocols. Crucially, there was no rebound of viral load for two months following treatment cessation of ABX464 whereas viral load increased dramatically just one week after ART treatment. A phase I study conducted in healthy volunteers has demonstrated that a single administration of ABX464 was well tolerated up to 150 mg.

Oral Abstracts

(a) Reconstituted SCID mice were infected with JRCSF HIV-1 strain by intraperitoneal injection. Control group received by gavage labrafil and 5% DMSO (n=15) and treated group 20mg/kg b.i.d of ABX464 in labrafil and 5% DMSO (n=14) for 15 days. (b) FACS analysis was performed on peritoneal wash at day 15 post-treatment to assess the CD8/CD4 ratio. (c) Engrafted NSG humanized mice were treated by oral gavage with ABX464 at either 20 mg or 40 mg/kg once a day for 30 days and indicated lymphocyte populations were monitored by FACS analysis. (d) NSG humanized mice were infected with the YU2 HIV-1 virus and treated either by oral gavage with SPL-464 at 40 mg/kg once a day for 30 days or by HAART (3TC-Tenofovir-Raltegravir and AZT).

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CROI 2015