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Clinical Trial
. 2019 Mar 1;33(3):425-431.
doi: 10.1097/QAD.0000000000002083.

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

Sara Moron-Lopez  1 , Peggy Kim  1 , Ole S Søgaard  2   3 , Martin Tolstrup  2   3 , Joseph K Wong  1 , Steven A Yukl  1
Affiliations
Clinical Trial

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

Sara Moron-Lopez et al. AIDS. .

Abstract

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.

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Conflict of interest statement

Conflict of interest:

Bionor Pharma sponsored the clinical study from which these samples were derived and contributed to the design of the clinical trial. The funders had no role in data collection and analysis, decision to publish, or preparation of the manuscript. The remaining authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.. HIV transcriptional profile, HIV DNA, and blocks to HIV transcription before and after romidepsin therapy.
(A) Diagram of the assays used to characterize the HIV transcriptional profile; (B) Dynamics of each HIV transcript per million PBMCs; (C) Dynamics of total HIV DNA; and (D) Changes in transcriptional interference, elongation, completion, and multiple-splicing. Each color represents a different individual from the REDUC part B study; bars represent medians. Determinations below the limit of quantification (LOQ) are represented as solid dots.
Figure 2.
Figure 2.. Association between HIV DNA and HIV transcription profile before and after romidepsin infusion, and time to rebound after ATI and subsequent suppression.
(A) Spearman correlations between the total HIV DNA per million PBMCs and time to rebound (measured as days to VL>50 copies/ml and VL>1,000 copies/ml of plasma), and time to suppression (quantified as days to VL<50 copies/ml of plasma after ART reinitiation); (B) Spearman correlations between the different HIV transcripts per million PBMCs and time to viral rebound (measured as days to VL>50 copies/ml and VL>1,000 copies/ml of plasma); and (C) Spearman correlations between total HIV DNA per million PBMCs and the different HIV transcripts per million PBMCs. Each color represents a different individual from the REDUC part B study.
See this image and copyright information in PMC

References

    1. Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A 1997; 94(24):13193–13197. - PMC - PubMed
    1. Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina CA, et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 1997; 278(5341):1291–1295. - PubMed
    1. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997; 278(5341):1295–1300. - PubMed
    1. Joos B, Fischer M, Kuster H, Pillai SK, Wong JK, Boni J, et al. HIV rebounds from latently infected cells, rather than from continuing low-level replication. Proc Natl Acad Sci U S A 2008; 105(43):16725–16730. - PMC - PubMed
    1. Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 2012; 487(7408):482–485. - PMC - PubMed

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