title: Concentrations of Pro-Inflammatory Cytokines Are Not Associated with Senescence Marker p16INK4a or Predictive of Intracellular Emtricitabine/Tenofovir Metabolite and Endogenous Nucleotide Exposures in Adults with HIV Infection.
abstract: OBJECTIVE
  As the HIV-infected population ages, the role of cellular senescence and inflammation on co-morbid conditions and pharmacotherapy is increasingly of interest. p16INK4a expression, a marker for aging and senescence in T-cells, is associated with lower intracellular concentrations of endogenous nucleotides (EN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs). This study expands on these findings by determining whether inflammation is contributing to the association of p16INK4a expression with intracellular metabolite (IM) exposure and endogenous nucleotide concentrations.
  
  
  METHODS
  Samples from 73 HIV-infected adults receiving daily tenofovir/emtricitabine (TFV/FTC) with either efavirenz (EFV) or atazanavir/ritonavir (ATV/r) were tested for p16INK4a expression, and plasma cytokine and intracellular drug concentrations. Associations between p16INK4a expression and cytokine concentrations were assessed using maximum likelihood methods, and elastic net regression was applied to assess whether cytokines were predictive of intracellular metabolite/endogenous nucleotide exposures.
  
  
  RESULTS
  Enrolled participants had a median age of 48 years (range 23-73). There were no significant associations between p16INK4a expression and cytokines. Results of the elastic net regression showed weak relationships between IL-1Ra and FTC-triphosphate and deoxyadenosine triphosphate exposures, and MIP-1β, age and TFV-diphosphate exposures.
  
  
  CONCLUSIONS
  In this clinical evaluation, we found no relationships between p16INK4a expression and cytokines, or cytokines and intracellular nucleotide concentrations. While inflammation is known to play a role in this population, it is not a major contributor to the p16INK4a association with decreased IM/EN exposures in these HIV-infected participants.
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Maas
authors.affiliation: Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Owen
authors.initials: O
authors.lastname: Francis
authors.affiliation: School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Katie R
authors.initials: KR
authors.lastname: Mollan
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lee
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Mackenzie L
authors.initials: ML
authors.lastname: Cottrell
authors.affiliation: School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Heather M A
authors.initials: HM
authors.lastname: Prince
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Sykes
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Trezza
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Chad
authors.initials: C
authors.lastname: Torrice
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: White
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Malone
authors.affiliation: Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hudgens
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Julie B
authors.initials: JB
authors.lastname: Dumond
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000378:metabolism / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D000068679:Emtricitabine / Q000378:metabolism* / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009711:Nucleotides / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use; D000068698:Tenofovir / Q000378:metabolism* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016207:Cytokines; D009711:Nucleotides; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000068679:Emtricitabine; D019438:Ritonavir