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

ObjectivesAs 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.MethodsSamples 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.ResultsEnrolled 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.ConclusionsIn 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.

Intracellular Tenofovir and Emtricitabine Concentrations in Younger and Older Women with HIV Receiving Tenofovir Disoproxil Fumarate/Emtricitabine

“…We have shown that expression of p16 INK4a , a tumor suppressor gene associated with cellular senescence (25), is associated with increased tenofovir diphosphate (TFVdp) and emtricitabine triphosphate (FTCtp) intracellular clearance, i.e., lower intracellular concentrations, among HIV-positive men and women ranging in age from 20 to 73 years (26,27). We did not, however, find associations between p16 INK4a expression and a panel of proinflammatory cytokines in our virally suppressed population (28).…”

“…First, log-rank tests were performed to compare the distributions of the ratios. This approach was used as some of the ratios had observations below the limit of quantification (BLQ) (28). To right-censor these observations and allow use of a log-rank test, ratios were subtracted from a value arbitrarily larger than the maximum of the ratios, as suggested by Gillespie et al (29).…”

Cellular Senescence Biomarker p16INK4a+ Cell Burden in Thigh Adipose is Associated With Poor Physical Function in Older Women

“…p16 INK4a + cells isolated from adipose tissue exhibit elevated expression of pro-inflammatory senescence-associated secretory phenotype (SASP) products compared to cells from the same tissues not expressing p16 INK4a (3,11,26,28). However, the relation between p16 INK4a and the SASP is nuanced and by p16 INK4a overexpression may not consistently activate a SASP (30,31). Whether driven through SASP-dependent mechanisms or not, collectively these data support a model in which p16 INK4a + cells shorten healthy lifespan and negatively impact function with age in rodents.…”

Correlations between age, functional status, and the senescence-associated proteins HMGB2 and p16INK4a

“…Such markers are important to evaluate individual variation in the rate of aging in human populations and the impact of interventions that target the aging process. Efforts to estimate the burden of senescence have focused on RNA levels of the cell cycle regulator, p16 INK4a , and mediators of the senescence-associated secretory phenotype (SASP) (Sanoff et al 2014;Maas et al 2016). These mediators include inflammatory cytokines such as IL-6 and IL-8.…”