title: HIV-1 transcriptional activity during frequent longitudinal sampling in aviremic patients on antiretroviral therapy.
abstract: BACKGROUND
  HIV-1 transcription during suppressive antiretroviral therapy (ART) is not well understood. This is problematic as latency-reactivating agent-based HIV-1 eradication trials utilize changes in viral transcription as an efficacy biomarker.
  
  
  METHODS
  We conducted an observational cohort study enrolling aviremic, HIV-1-infected adults on long-term ART. Cell-associated unspliced (CA-US) HIV-1 RNA and total HIV-1 DNA were quantified in unfractionated CD4 T cells monthly for a total of six consecutive visits. Random-effects models were used to determine the following: (i) proportion of variation attributable to intra-individual versus inter-individual changes; (ii) range estimate for random samples from any participant or cohort-matched individual (95% prediction interval); and (iii) range estimate for random samples from the same person (95% variation intervals expressed as fold change).
  
  
  RESULTS
  Among our cohort of 26 HIV-1 patients, 10.4% of variation in CA-US HIV-1 RNA was attributable to intra-individual fluctuations. Similarly, intra-individual changes also accounted for minor proportions of the variation in total HIV-1 DNA (5.1%) and RNA/DNA (28.3%). The 95% prediction interval (per 10 CD4 T cells) for CA-US HIV-1 RNA and HIV-1 DNA were each approximately 2 log10. Finally, model-derived 95% variation intervals indicate that spontaneous changes above 2.11-fold in CA-US HIV-1 RNA would occur in less than 5% of repeated measurements in an individual on long-term ART.
  
  
  CONCLUSIONS
  The individual CA-US HIV-1 RNA levels are remarkably stable during ART. Importantly, the observed variations were less than the reported changes for latency-reactivating agent trials. These data will serve as a foundation for planning and interpreting future eradication trials.
authors.affiliation: aDepartment of Infectious Diseases, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99- 8200 Aarhus N, Denmark bAarhus Institute for Advanced Studies, Nordre Ringgade 1, 8000 Aarhus C, Denmark cInstitute of Clinical Medicine, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N. Denmark. *Steffen Leth, Rasmus Nymann and Sofie Jørgensen contributed equally to this article.
authors.forename: Steffen
authors.initials: S
authors.lastname: Leth
authors.forename: Rasmus
authors.initials: R
authors.lastname: Nymann
authors.forename: Sofie
authors.initials: S
authors.lastname: Jørgensen
authors.forename: Rikke
authors.initials: R
authors.lastname: Olesen
authors.forename: Thomas Aagaard
authors.initials: TA
authors.lastname: Rasmussen
authors.forename: Lars
authors.initials: L
authors.lastname: Østergaard
authors.forename: Paul W
authors.initials: PW
authors.lastname: Denton
authors.forename: Martin
authors.initials: M
authors.lastname: Tolstrup
authors.forename: Ole Schmeltz
authors.initials: OS
authors.lastname: Søgaard
mesh_terms: D000328:Adult; D000368:Aged; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002986:Clinical Trials as Topic; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000254:growth & development*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D044966:Anti-Retroviral Agents; D004279:DNA, Viral; D012367:RNA, Viral