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Clinical Trial
. 2016 Dec 30;11(12):e0168709.
doi: 10.1371/journal.pone.0168709. eCollection 2016.

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

Free PMC article
Clinical Trial

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

Brian M Maas et al. PLoS One. .
Free PMC article


Objectives: 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.

Conflict of interest statement

Katie R Mollan previously received research support from grants awarded to UNC from Merck, AbbVie, and Gilead. Christine Trezza was a post-doctoral fellow at UNC at the time of study conduct and is currently employed at ViiV Healthcare. These competing interests do not alter our adherence to the data sharing policies; the work itself was funded by non-industry sources and as such, is the property of the University of North Carolina at Chapel Hill.


Fig 1
Fig 1. Boxplots of measured cytokine concentrations.
Fig 2
Fig 2. Scatterplots of p16INK4a expression versus cytokine concentrations.
Observations with quantifiable cytokine concentrations are displayed as blue circles; concentrations below the LLQ are displayed as red + symbols. Cytokine concentrations and p16INK4a expression were natural-log transformed and log2 transformed, respectively. A descriptive LOESS curve is plotted handling below LLQ values as observed. Correlation estimates were less than or equal to 0.22 for all associations (Table 1). LLQ, lower limit of quantification.

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