title: Cell cycle kinetic dysregulation in HIV-infected normal lymphocytes.
abstract: BACKGROUND
  Viruses alter cellular gene transcription and protein binding at many steps critical for cell cycle regulation to optimize the milieu for productive infection. Reasoning that virus-host cell interactions would result in perturbations of cell cycle kinetics, measurement of the duration of the phases of the cell cycle in normal T lymphocytes infected with human immunodeficiency virus (HIV) was undertaken.
  
  
  METHODS
  Flow cytometric measurement of bromodeoxyuridine-labeled and DNA content-stained cells at multiple points through the cell cycle allowed estimation of the fraction of cells in each phase, the potential doubling-time, and the durations of S and G(2)/M phases. Separate analysis of the HIV(+) and HIV(-) populations within the infected cultures was performed based on intracellular, anti-HIV core p24 antibody labeling. A novel mathematical model, which accounted for cell loss, was developed to estimate cell cycle phases.
  
  
  RESULTS
  (a) S phase was prolonged in the HIV-1(SF2)-infected cells compared with control. (b) This delay in S phase was due to delay in the population of cells not expressing HIV-1 antigens (p24 negative). (c) Accumulation of cells in G(2)/M phase was confirmed in HIV-1-infected cultures and was proportional to the level of infection as measured by p24 fluorescent intensity. However, all mock and HIV-1-infected populations predicted to proceed through cell division demonstrated similar G(2)/M-phase durations. (c) Potential doubling times were longer in the infected cultures; in contrast, the p24(+) subpopulations accounted for this delay. This suggests an isolated delay in the G(0)/G(1) phase for that population of cells.
  
  
  CONCLUSIONS
  Multiple phases of host cell cycle durations were affected by HIV-1(SF2) infection in this in vitro model, suggesting novel HIV-1 pathogenesis mechanisms. Prolonged S-phase durations in HIV-1 infected/p24(-) and G(0)/G(1)-phase durations in HIV-1 infected/p24(+) subpopulations require further study to identify mechanistic pathways.
authors.affiliation: Department of Internal Medicine, University of California-Davis, Sacramento, California. david.asmuth@ucdmc/ucdavis.edu
authors.forename: David M
authors.initials: DM
authors.lastname: Asmuth
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Li
authors.forename: Lisa
authors.initials: L
authors.lastname: Reece
authors.forename: Nicholas H A
authors.initials: NH
authors.lastname: Terry
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pollard
authors.forename: Mostafa
authors.initials: M
authors.lastname: Nokta
authors.forename: James F
authors.initials: JF
authors.lastname: Leary
authors.forename: R Allen
authors.initials: RA
authors.lastname: White
mesh_terms: D001973:Bromodeoxyuridine / Q000737:chemistry; D002453:Cell Cycle / Q000502:physiology*; D004247:DNA / Q000032:analysis; D005434:Flow Cytometry; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000502:physiology / Q000821:virology*; D008954:Models, Biological
chemical_list: D004247:DNA; D001973:Bromodeoxyuridine