title: Integrated HIV DNA accumulates prior to treatment while episomal HIV DNA records ongoing transmission afterwards.
abstract: OBJECTIVE
  We investigated the dynamics of HIV RNA and HIV DNA levels after the commencement of raltegravir-based antiretroviral therapy (ART) in primary (PHI) and chronically HIV-infected (CHI) individuals (the PINT study).
  
  
  METHODS
  We recruited 8 PHI and 8 CHI ART-naive individuals who commenced a 1-year combination regimen of Truvada and the integrase inhibitor raltegravir.
  
  
  METHODS
  Nonlinear mixed effects modelling was used to determine multiphasic decay of plasma HIV RNA levels (pVL), as well as dynamics of total, episomal [2-long terminal repeats (LTR)] and integrated HIV DNA in CD4 T cells from peripheral blood.
  
  
  RESULTS
  Although pVL decreased faster through first and second phase for PHI individuals there was no difference in the final level reaching a mean of 9 copies/ml by week 16 that was maintained thereafter. Total HIV DNA and integrated HIV DNA levels from CHI patients were significantly higher than from PHI patients. However, at no time did 2-LTR levels differ between groups. Of note, 2-LTR circles exhibited an initial increase peaking at week 3 followed by biphasic decay with a half-life of 29 days. Second phase integrated HIV DNA levels were significantly correlated with duration of infection and consistent with this form of infection occurring at approximately 100 000 integration events per day in the absence of ART, achieving its 50% level 2 years after infection.
  
  
  CONCLUSIONS
  Integrated HIV DNA levels accumulate with duration of untreated HIV infection. The relatively short half-life and high levels of 2-LTR circles after 1 year support continued HIV transmission during ART.
authors.affiliation: School of Mathematics and Statistics, University of New South Wales, Sydney, New South Wales, Australia. J.Murray@unsw.edu.au
authors.forename: John M
authors.initials: JM
authors.lastname: Murray
authors.forename: Kristin
authors.initials: K
authors.lastname: McBride
authors.forename: Christoph
authors.initials: C
authors.lastname: Boesecke
authors.forename: Michelle
authors.initials: M
authors.lastname: Bailey
authors.forename: Janaki
authors.initials: J
authors.lastname: Amin
authors.forename: Kazuo
authors.initials: K
authors.lastname: Suzuki
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: John J
authors.initials: JJ
authors.lastname: Zaunders
authors.forename: Sean
authors.initials: S
authors.lastname: Emery
authors.forename: David A
authors.initials: DA
authors.lastname: Cooper
authors.forename: Kersten K
authors.initials: KK
authors.lastname: Koelsch
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
mesh_terms: D015153:Blotting, Western; D018791:CD4 Lymphocyte Count; D002908:Chronic Disease; D004279:DNA, Viral / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004338:Drug Combinations; D004359:Drug Therapy, Combination / Q000379:methods; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D012367:RNA, Viral / Q000378:metabolism*; D000068898:Raltegravir Potassium; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004279:DNA, Viral; D004338:Drug Combinations; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D019428:HIV Integrase Inhibitors; D009943:Organophosphorus Compounds; D011760:Pyrrolidinones; D012367:RNA, Viral; D003841:Deoxycytidine; D000068898:Raltegravir Potassium