title: HIV-1 CNS in vitro infectivity models based on clinical CSF samples.
abstract: BACKGROUND
  The concentration of antiretrovirals in CSF is often utilized as a surrogate for CNS drug exposure. This measurement does not consider pharmacodynamic or combinative effects of ART. We have developed a novel endpoint measurement to assess antiretroviral activity of CSF from subjects on ART.
  
  
  METHODS
  CSF samples were obtained from patients receiving tenofovir/emtricitabine (245/200 mg once daily) with either rilpivirine (25 mg once daily) or lopinavir/ritonavir/maraviroc (400/100/150 mg twice daily) and HIV-uninfected controls. Antiviral activity of ART-containing CSF was assessed in cell cultures using PBMCs and neuro-derived glial (U87) and astrocyte (373) cell lines. Infectivity model half-maximal inhibitory concentration (IMIC50) values were calculated and expressed as -log2IMIC50. Results were correlated with CSF antiretroviral concentrations.
  
  
  RESULTS
  Compared with controls, CSF from both ART studies demonstrated in vitro antiretroviral activity in all models. CSF antiretroviral activity of patients on lopinavir/ritonavir/maraviroc was significantly greater than that of patients on rilpivirine [-log2IMIC50 (95% CI) 4.82 (4.74-4.89) versus 3.43 (3.33-3.54) in PBMCs, 3.06 (2.98-3.15) versus 2.56 (2.46-2.65) in U87 cells and 6.00 (6.11-5.88) versus 4.90 (5.09-4.72) in 373 cells, respectively]. Positive correlations were observed for individual CSF antiretroviral activity in different cellular models with CSF concentrations of rilpivirine (P = 0.040 in 373 cells) and lopinavir (P = 0.048 in 373 cells), but not maraviroc.
  
  
  CONCLUSIONS
  Antiviral activity of CSF from patients on ART was successfully calculated and was greater with a regimen containing four active drugs compared with three active drugs. The use of neuro-derived cell lines alongside PBMCs to assess the effect of ART on CSF may act as a useful future clinical research tool.
authors.affiliation: Department of Infectious Diseases and Immunity, Faculty of Medicine, Imperial College, London, UK Department of HIV and Genitourinary Medicine, Imperial College Healthcare NHS Trust, St Mary's Hospital, London, UK b.mora-peris@imperial.ac.uk.
authors.forename: Borja
authors.initials: B
authors.lastname: Mora-Peris
authors.affiliation: Department of Infectious Diseases and Immunity, Faculty of Medicine, Imperial College, London, UK Department of HIV and Genitourinary Medicine, Imperial College Healthcare NHS Trust, St Mary's Hospital, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Winston
authors.affiliation: Department of Infectious Diseases and Immunity, Faculty of Medicine, Imperial College, London, UK Department of HIV and Genitourinary Medicine, Imperial College Healthcare NHS Trust, St Mary's Hospital, London, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Garvey
authors.affiliation: Department of Clinical and Molecular Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Else
authors.affiliation: Department of Infectious Diseases and Immunity, Faculty of Medicine, Imperial College, London, UK.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
authors.affiliation: Department of Infectious Diseases and Immunity, Faculty of Medicine, Imperial College, London, UK.
authors.forename: Carolina
authors.initials: C
authors.lastname: Herrera
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000032:analysis* / Q000494:pharmacology; D023241:Antiretroviral Therapy, Highly Active; D001253:Astrocytes / Q000502:physiology / Q000821:virology; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002555:Cerebrospinal Fluid / Q000737:chemistry*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009457:Neuroglia / Q000502:physiology / Q000821:virology; D014776:Virus Cultivation
chemical_list: D019380:Anti-HIV Agents