期刊
AIDS
卷 33, 期 3, 页码 425-431出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0000000000002083
关键词
HIV-1; humans; latency; RNA; RNA splicing; romidepsin; transcription
资金
- National Institute of Allergy and Infectious Diseases at the National Institutes of Health [1R01AI132128, R56AI116342, R33AI116218, R56AI091573, U19AI096109]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health [1R01DK108349]
- U.S. Department of Veterans Affairs [IK2 CX000520, I01 BX000192]
- American Foundation for AIDS Research (amfAR) Institute for HIV Cure Research [109301]
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. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.
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