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Romidepsin-induced HIV-1 viremia during effective antiretroviral therapy contains identical viral sequences with few deleterious mutations

Winckelmann, Anni; Barton, Kirston; Hiener, Bonnie; Schlub, Timothy E.; Shao, Wei; Rasmussen, Thomas A.; Østergaard, Lars; Søgaard, Ole S.; Tolstrup, Martin; Palmer, Sarah

doi: 10.1097/QAD.0000000000001400
Clinical Science

Objective: To investigate the origin of the HIV-1 viremia induced by the latency-reversing agent romidepsin.

Design: Six individuals on suppressive antiretroviral therapy received romidepsin administered intravenously once weekly for 3 consecutive weeks. CD4+ T cells were obtained at baseline, following the second and third romidepsin infusion, and 10 weeks after the final romidepsin treatment. Plasma samples were collected 24 and 72 h after romidepsin infusions.

Methods: Single-genome sequencing of the env and p24-RT region was used to genetically characterize the virus from proviral DNA, the transcribed cell-associated RNA and the plasma RNA pool.

Results: In three of six participants with available plasma samples we identified plasma HIV-1 RNA sequences that were identical to DNA and/or cell-associated RNA sequences from peripheral blood CD4+ T cells. In two participants, plasma RNA sequences contained expansions of identical sequences, corresponding to 62 and 100% of the total sequences, respectively. Plasma HIV-1 RNA had very low amounts of defective viruses compared to cell-associated RNA (odds ratio 20.85, P < 0.001) and to DNA (odds ratio 7.07, P = 0.011) during romidepsin therapy.

Conclusions: Romidepsin induced transcription from proviruses in peripheral blood cells, which contributed to viremia in patients on suppressive therapy. The intermingling of these cell-associated HIV-1 RNA with DNA sequences indicates transcription from a diverse range of proviruses, but the expansions of identical viral plasma sequences with few defects indicate that the romidepsin-induced viremia arises from intact proviruses with highly similar or identical genetic backgrounds.

aCentre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead, New South Wales, Australia

bThe Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark

cSydney School of Public Health, Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia

dAdvanced Biomedical Computing Center, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick

eHIV Dynamics and Replication Program, National Cancer Institute, Frederick, Maryland, USA

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

Correspondence to Anni Winckelmann, Department of Infectious Diseases, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark. E-mail: anniw@clin.au.dk.

Received 22 November, 2016

Revised 22 December, 2016

Accepted 28 December, 2016

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