title: Biphasic decay kinetics suggest progressive slowing in turnover of latently HIV-1 infected cells during antiretroviral therapy.
abstract: BACKGROUND
  Mathematical models based on kinetics of HIV-1 plasma viremia after initiation of combination antiretroviral therapy (cART) inferred HIV-infected cells to decay exponentially with constant rates correlated to their strength of virus production. To further define in vivo decay kinetics of HIV-1 infected cells experimentally, we assessed infected cell-classes of distinct viral transcriptional activity in peripheral blood mononuclear cells (PBMC) of five patients during 1 year after initiation of cART RESULTS: In a novel analytical approach patient-matched PCR for unspliced and multiply spliced viral RNAs was combined with limiting dilution analysis at the single cell level. This revealed that HIV-RNA+ PBMC can be stratified into four distinct viral transcriptional classes. Two overlapping cell-classes of high viral transcriptional activity, suggestive of a virion producing phenotype, rapidly declined to undetectable levels. Two cell classes expressing HIV-RNA at low and intermediate levels, presumably insufficient for virus production and occurring at frequencies exceeding those of productively infected cells matched definitions of HIV-latency. These cells persisted during cART. Nevertheless, during the first four weeks of therapy their kinetics resembled that of productively infected cells.
  
  
  CONCLUSIONS
  We have observed biphasic decays of latently HIV-infected cells of low and intermediate viral transcriptional activity with marked decreases in cell numbers shortly after initiation of therapy and complete persistence in later phases. A similar decay pattern was shared by cells with greatly enhanced viral transcriptional activity which showed a certain grade of levelling off before their disappearance. Thus it is conceivable that turnover/decay rates of HIV-infected PBMC may be intrinsically variable. In particular they might be accelerated by HIV-induced activation and reactivation of the viral life cycle and slowed down by the disappearance of such feedback-loops after initiation of cART.
authors.affiliation: University Hospital Zürich, Division of Infectious Diseases, Rämistrasse 100, 8092 Zürich, Switzerland. marek.fischer@usz.ch
authors.forename: Marek
authors.initials: M
authors.lastname: Fischer
authors.forename: Beda
authors.initials: B
authors.lastname: Joos
authors.forename: Barbara
authors.initials: B
authors.lastname: Niederöst
authors.forename: Philipp
authors.initials: P
authors.lastname: Kaiser
authors.forename: Roland
authors.initials: R
authors.lastname: Hafner
authors.forename: Viktor
authors.initials: V
authors.lastname: von Wyl
authors.forename: Martina
authors.initials: M
authors.lastname: Ackermann
authors.forename: Rainer
authors.initials: R
authors.lastname: Weber
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology*; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents