title: Romidepsin-induced HIV-1 viremia during effective antiretroviral therapy contains identical viral sequences with few deleterious mutations.
abstract: To investigate the origin of the HIV-1 viremia induced by the latency-reversing agent romidepsin.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Anni
authors.initials: A
authors.lastname: Winckelmann
authors.forename: Kirston
authors.initials: K
authors.lastname: Barton
authors.forename: Bonnie
authors.initials: B
authors.lastname: Hiener
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Schlub
authors.forename: Wei
authors.initials: W
authors.lastname: Shao
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rasmussen
authors.forename: Lars
authors.initials: L
authors.lastname: Østergaard
authors.forename: Ole S
authors.initials: OS
authors.lastname: Søgaard
authors.forename: Martin
authors.initials: M
authors.lastname: Tolstrup
authors.forename: Sarah
authors.initials: S
authors.lastname: Palmer
mesh_terms: D061605:Administration, Intravenous; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D018791:CD4 Lymphocyte Count; D047630:Depsipeptides / Q000008:administration & dosage*; D014644:Genetic Variation; D016655:HIV Core Protein p24 / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D009154:Mutation; D011533:Proviruses / Q000145:classification / Q000235:genetics / Q000302:isolation & purification; D017422:Sequence Analysis, DNA; D014766:Viremia / Q000139:chemically induced / Q000821:virology*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D044966:Anti-Retroviral Agents; D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D016655:HIV Core Protein p24; D054299:env Gene Products, Human Immunodeficiency Virus; C087123:romidepsin; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase