Antiretroviral treatment (ART) intensification and disruption of latent HIV infection (reversal or silencing) have been suggested as strategies to eradicate HIV. ABX464 (AbiVax) is a novel antiviral that binds to the cap binding complex, interfering with splicing and Rev-mediated export of newly transcribed HIV RNA. ABX464 has been shown to inhibit HIV RNA biogenesis in vitro and delayed viral rebound in a humanized mouse model. We investigated the effect of ABX464 on the HIV transcription profile and total and intact HIV DNA in circulating CD4+ T cells from ART-suppressed participants enrolled in the ABIVAX-005 clinical trial (NCT02990325).
Eleven participants on suppressive ART were treated daily with 150mg of ABX464 for 4 weeks. Peripheral CD4+ T cells from nine study participants were available for HIV transcription profile and reservoir size analysis. Total HIV DNA, intact HIV DNA (IPDA), and Read-through, total/initiated, 5’elongated, unspliced, polyadenylated and multiply-spliced HIV transcripts were quantified at weeks 0, 4 and 8 using ddPCR.
We observed a significant decrease in the total HIV DNA (p=0.008, median fold-change=0.8) and a lower median level of intact HIV DNA (p=n.s., median fold-change=0.8) after ABX464 treatment (wk0 vs. wk4). However, intact HIV DNA increased significantly (p=0.008, fold-change=1.6) after ABX464 discontinuation (wk4 vs. wk8). After 4 weeks of ABX464 treatment, we observed a decrease in total initiated HIV RNA per million CD4+ T cells and per provirus (HIV RNA/HIV DNA) (p=0.05, median fold-change=0.7; p=0.004, median fold-change=0.5, respectively), a trend towards a decrease in the 5’elongated HIV RNA per provirus (p=0.07, median fold-change=0.5), and a lower median level of unspliced HIV RNA (p=n.s., median fold-change=0.6), but no decrease in polyadenylated or multiply-spliced HIV RNA. However, 5’elongated HIV RNA per million CD4+ T cells increased significantly (p=0.04, fold-change=1.4) after ABX464 discontinuation (wk4 vs. wk8).
In this substudy, ABX464 had a dual effect of decreasing total HIV DNA (and possibly intact proviruses) and decreasing the amount of HIV transcription per provirus, although these changes were reversed after drug discontinuation. Our data suggest that ABX464 acts as an ART intensifier in vivo. To further characterize its specific mechanism of inhibiting HIV transcription, long-term administration of ABX464 in a larger cohort should be studied.