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CHARACTERIZATION OF HIV-1 TRANSCRIPTION PROFILE AFTER ROMIDEPSIN THERAPY IN VIVO
Sara Moron-Lopez1, Peggy Kim2, Ole S. Søgaard3, Martin Tolstrup3, Joseph K. Wong2, Steven A. Yukl2
1University of California San Francisco, San Francisco, CA, USA,2San Francisco VA Medical Center, San Francisco, CA, USA,3Aarhus University Hospital, Aarhus, Denmark
Reversing HIV-1 latency has been suggested as a strategy to eradicate HIV-1. We investigated the effect of romidepsin on the HIV transcription profile in participants from the REDUC part B clinical trial.
Seventeen participants on suppressive antiretroviral therapy were vaccinated with six doses of the therapeutic vaccine Vacc-4x followed by treatment with three doses of romidepsin. Samples from nine study participants were available for HIV transcription profile analysis. Read-through, total (TAR), elongated (longLTR), polyadenylated (polyA) and multiply-spliced (TatRev) HIV transcripts and total HIV DNA were quantified at baseline (visit1) and 4 hours after the second (visit 10b) and third (visit 11b) romidepsin infusions, using droplet digital PCR.
We observed a significant increase in read-through (1.7-fold, p=0.02), total (1.9-fold, p<0.01), elongated (2.4-fold, p<0.01) and polyadenylated (1.9-fold, p=0.03) HIV RNA/106 PBMCs after the second romidepsin infusion (visit 10b), and a 1.9-fold increase in elongated transcripts after the third romidepsin infusion (visit 11b) (p<0.01). No significant changes were observed in multiply-spliced HIV RNA or HIV DNA. No change was observed in the ratio of read-through/total HIV transcripts. The ratio of elongated/total HIV RNA increased after both the second and third romidepsin infusions (p=0.02), while the ratio of polyadenylated/elongated HIV decreased after the third infusion (p=0.02). A strong negative correlation was observed between HIV DNA and the time to rebound (VL>50copies/ml) at visit 1, 10b, and 11b (Rho=-0.81, -0.88, and -0.91; p=0.02, p<0.01, and p<0.01, respectively). Levels of all HIV RNAs tended to correlate negatively with the time to rebound. This association was strongest for the comparison between elongated transcripts and time to VL>1,000copies/ml after romidepsin administration (Rho=-0.78, p=0.03 at visit 10b; Rho=-0.77, p=0.03 at visit 11b).
In these patients, romidepsin increased early events in HIV transcription (initiation and especially elongation), but had less effect on later stages (completion, multiple splicing) that may be required for comprehensive latency reversal and cell killing. Without cell death, increased HIV transcription before or after latency reversal may hasten viral rebound after therapy interruption.