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Characterization of the HIV-1 transcription profile after romidepsin administration in ART-suppressed individuals

Moron-Lopez, Saraa; Kim, Peggya; Søgaard, Ole S.b,c; Tolstrup, Martinb,c; Wong, Joseph K.a; Yukl, Steven A.a

doi: 10.1097/QAD.0000000000002083
BASIC SCIENCE: CONCISE COMMUNICATION
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Objectives: 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.

Design: 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.

Methods: Read-through, total (TAR), elongated (longLTR), polyadenylated (polyA) and multiply-spliced (Tat-Rev) HIV transcripts and total HIV DNA were quantified at baseline (visit 1) and 4 h after the second (visit 10b) and third (visit 11b) romidepsin infusions.

Results: Read-through, total, elongated, and polyadenylated HIV transcripts increased after romidepsin infusion (P = 0.020, P = 0.0078, P = 0.0039, P = 0.027, respectively), but no 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 romidepsin (P = 0.016), whereas the ratio of polyadenylated/elongated HIV decreased. Both elongated HIV transcripts and total HIV DNA correlated negatively with the time to viral rebound after interruption of ART.

Conclusions: 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.

aSan Francisco Veterans Affairs (VA) Medical Center and University of California San Francisco (UCSF), 4150 Clement Street, 111W, San Francisco, California, USA

bThe Department of Infectious Diseases, Aarhus University Hospital

cInstitute of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Correspondence to Steven A. Yukl, MD, San Francisco Veterans Affairs (VA) Medical Center and University of California San Francisco (UCSF), 4150 Clement Street, 111W, San Francisco, CA 94121, USA. E-mail: steven.yukl@ucsf.edu

Received 11 September, 2018

Accepted 17 October, 2018

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