Expression of p16INK4a as a biomarker of T‐cell aging in HIV‐infected patients prior to and during antiretroviral therapy
Open accessAbstract
Summary: The p16INK4a tumor suppressor gene is a mediator of cellular senescence and has been suggested to be a biomarker of ‘molecular’ age in several tissues including T cells. To determine the association of both active and suppressed HIV infection with T‐cell aging, T‐cell p16INK4a expression was compared between 60 HIV+ suppressed subjects, 23 HIV+ untreated subjects, and 18 contemporaneously collected HIV‐negative controls, as well as 148 HIV‐negative historical samples. Expression did not correlate with chronologic age in untreated HIV+ patients, consistent with an effect of active HIV replication on p16INK4a expression. In patients on cART with suppressed viral loads, however, p16INK4a levels were similar to uninfected controls and correlated with chronologic age, with a trend toward an inverse correlation with CD4 count. These data show that p16INK4a is a reliable biomarker of T‐cell aging in HIV+ patients with suppressed viral loads and suggest that poor CD4 cell recovery on cART may be associated with increased T‐cell expression of p16INK4a, a marker of cellular senescence.
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- Findingown data
In a multivariate linear regression among HIV-positive patients with suppressed viral loads, age had a significant linear association with p16INK4a (partial correlation r=0.32, 95% CI 0.07 to 0.53, p=0.01).
“There was a significant linear association between age and p16INK4a (partial correlation r=0.32 [95% CI 0.07, 0.53], p=0.01)”
Quote in the paperSubstantial claim - Findingown data
Smoking was associated with a 0.56 increase in p16INK4a expression (95% CI 0.00 to 1.12, p=0.05) in the regression model.
“smoking was associated with a 0.56 (95% CI 0.00, 1.12, p=0.05) increase in p16INK4a expression”
Quote in the paperNot a substantial claim - Findingown data
Among untreated HIV-positive patients, chronological age did not correlate with T-cell p16INK4a levels (r=0.19, 95% CI -0.24 to 0.56, p=0.35).
“there was no correlation between chronological age and p16INK4a levels in untreated HIV+ patients (r=0.19 [95% CI −0.24, 0.56], p=0.35)”
Quote in the paperSubstantial claim - Findingown data
In HIV-positive patients with suppressed viral loads on cART, chronological age correlated with T-cell p16INK4a levels (r=0.29, 95% CI 0.04 to 0.51, p=0.02).
“Chronological age and p16INK4a levels were correlated in suppressed HIV+ patients (r=0.29 [95% CI 0.04, 0.51], p=0.02)”
Quote in the paperSubstantial claim - Findingown data
In untreated HIV-positive patients, age-adjusted T-cell p16INK4a expression was significantly higher than in HIV-negative controls (p=0.003).
“there was a significantly higher level of age-adjusted p16INK4a expression in HIV+ patients compared to HIV-negative controls (p=0.003)”
Quote in the paperSubstantial claim
- Findingown data
Age-adjusted T-cell p16INK4a expression did not differ significantly between HIV-positive patients on cART with suppressed viral loads and HIV-negative controls (p=0.49).
“There was no significant difference in age-adjusted p16INK4a expression between HIV+ suppressed and HIV-negative individuals (p=0.49)”
Quote in the paperSubstantial claim - Interpretationown data
Untreated HIV replication leads to p16INK4a expression substantially above the age-associated levels seen in uninfected individuals.
“These data suggest that untreated HIV replication leads to p16INK4a expression that is substantially above age-associated levels in uninfected individuals.”
Quote in the paperSubstantial claim - Interpretationown data
In untreated HIV-positive patients, p16INK4a expression is driven by HIV replication rather than by chronological age.
“These data suggest that p16INK4a expression in untreated HIV+ patients is driven by HIV replication rather than chronological age.”
Quote in the paperSubstantial claim - Premisecitation
Chronic HIV infection may induce some features of immunosenescence.
“chronic HIV infection may induce some features of immunosenescence”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Deeks 2011
Not checked in the free run.
- Interpretationown data
Poor CD4 cell recovery on cART may be associated with increased T-cell expression of p16INK4a, a marker of cellular senescence.
“suggest that poor CD4 cell recovery on cART may be associated with increased T-cell expression of p16INK4a, a marker of cellular senescence”
Quote in the paperSubstantial claim - Interpretationown data
p16INK4a is a reliable biomarker of T-cell aging in HIV-positive patients with suppressed viral loads.
“These data show that p16INK4a is a reliable biomarker of T cell aging in HIV+ patients with suppressed viral loads”
Quote in the paperSubstantial claim - Interpretationown data
Control of viral replication reestablishes the relationship between chronological age and p16INK4a levels.
“indicating that control of viral replication reestablishes this relationship”
Quote in the paperSubstantial claim - Interpretationown data
Effective antiretroviral treatment that suppresses HIV replication results in p16INK4a levels similar to age-adjusted levels in uninfected individuals.
“Our data also suggest that effective antiretroviral treatment that suppresses HIV replication results in p16INK4a levels similar to age-adjusted p16INK4a expression levels in uninfected individuals.”
Quote in the paperSubstantial claim - Interpretationreasoning
The results are consistent with the possibility that HIV replication is associated with premature T-cell senescence.
“these results are consistent with the possibility that HIV replication is associated with premature T-cell senescence”
Quote in the paperSubstantial claim
- The quote only partly states this claim. 1
- May combine two claims. 5
- Classified as probably not a substantial claim. 5
The quote only partly states this claim.
Findingown dataIn treated HIV-positive patients, after adjusting for age and smoking, there was a trend toward a negative association between CD4 count and p16INK4a expression (partial correlation r=-0.21, 95% CI -0.44 to 0.05, p=0.10).
“there was a trend toward a negative association between CD4 and p16INK4a expression in treated patients (partial correlation r=−0.21 [95% CI −0.44, 0.05], p=0.10)”
- Also stated in: § Results and Discussion · hedged
“p16INK4a expression was marginally associated with lower CD4 counts even when controlling for age in treated patients”
Quote in the paperNot a substantial claim- Also stated in: § Results and Discussion · hedged
May combine two claims.
Findingown dataAfter adjusting for age and smoking, gender and race were not significantly associated with p16INK4a expression (p>0.2 for each).
“Gender and race were not significantly associated with p16INK4a (p>0.2 for either variable) after adjusting for age and smoking”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAge-adjusted p16INK4a levels differed significantly between suppressed and untreated HIV-positive patients (p=0.04), but the difference was only marginally significant after adjusting for smoking and CD4 count (p=0.10) and not significant after adjusting for smoking and CD4/CD8 ratio (p=0.39).
“Comparison of the suppressed and untreated HIV+ patients demonstrated a significant difference in age-adjusted p16INK4a levels (p=0.04); however, this difference was only marginally significant after adjusting for smoking and CD4 count (p=0.10), and not significant after adjusting for smoking and CD4/CD8 ratio (p=0.39)”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisecitationp16INK4a expression increases exponentially with age in most tissues across every mammalian species tested so far.
“expression of p16INK4a increases exponentially with age in most tissues in every mammalian species thus far tested”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sharpless and DePinho, 2007
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Premisecitationp16INK4a expression in human peripheral T-cells increases with chronological age and with age-modifying factors and interventions such as smoking and sedentary lifestyle.
“Expression of p16INK4a in human peripheral T-cells increases with chronologic age as well as age-modifying factors and interventions (e.g. smoking and sedentary lifestyle)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Liu et al., 2009
Not checked in the free run.
- cites Muss et al., 2011
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitationp16INK4a appears to play a causal role in the age-associated replicative decline of several tissues, including T-cells.
“appears to play a causal role in the age-associated replicative decline of several tissues, including T-cells”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Liu et al., 2011
Not checked in the free run.
Probably not a substantial claim: may not pass S1 (asserted), S4 (based). May combine two claims.
Study design and conductown dataThe analyses controlled for potential confounding by adjusting for age, smoking, CD4 count and CD4/CD8 ratio, including a multivariate linear regression with age, smoking and CD4 as predictors of p16INK4a in suppressed patients.
“A multivariate linear regression model was fit with age, smoking and CD4 as predictor variables and p16INK4a as the response variable in HIV+ patients with suppressed viral loads.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationImmune function and T-cell replicative capacity decline with age.
“Immune function and T-cell replicative capacity decline with age”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Haynes and Maue, 2009
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAblation of p16INK4a-expressing cells in genetically engineered mice delays some age-related phenotypes such as cataracts and sarcopenia.
“Ablation of p16INK4a-expressing cells in genetically engineered mice delays some age-related phenotypes such as cataracts and sarcopenia”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Baker et al., 2011
Not checked in the free run.
The paper relies on this without support.
Before this study, the effect of HIV infection on T-cell p16INK4a expression was unknown.
“but the effects of HIV infection on this biomarker are unknown”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HAART-treated HIV patients have p16 levels comparable to uninfected controls in T cells.
“HAART‐treated HIV patients displayed p16 levels comparable to uninfected controls in T cells (Nelson et al, 2012; Pereira Ribeiro et al, 2016).”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Nelson et al, 2012
p16 levels are increased in CD4+ T cells, but not CD8+ T cells, in HIV patients untreated with HAART compared to uninfected individuals.
“However, p16 levels are increased in CD4+, but not CD8+, T cells in HIV patients untreated with HAART, compared to uninfected individuals (Nelson et al, 2012; Pereira Ribeiro et al, 2016).”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Nelson et al, 2012
Increased p16(INK4a) expression in T cells of HIV-infected subjects and an inverse relationship with therapy-induced CD4 T cell recovery suggest p16 as a possible biomarker of T cell aging.
“Increased expression of p16(INK4a) in T cells of HIV-infected subjects and an inverse relationship between p16(INKp4a) expression and therapy-induced CD4 T cells recovery has suggested a possible role of this senescence-associated gene as a biomarker of T cell aging [44].”
From T-cell aging in rheumatoid arthritis (2014) · cites this paper as [44]
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Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670 · cited 1× · see citing works
“Ablation of p16INK4a-expressing cells in genetically engineered mice delays some age-related phenotypes such as cataracts and sarcopenia (Baker et al., 2011).”
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- Authors
- Nelson, J. A. E., Krishnamurthy, J., Menezes, P., Liu, Y., Hudgens, M. G., Sharpless, N. E., & Eron, J. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Nelson, Julie A. E.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2012-09-16
- Volume
- 11
- Issue
- 5
- Pages
- 916-918
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC3697001
- OpenAlex
- W2160880676
- Cited by
- 66
- References
- 10
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 11 · 2019: 5 · 2018: 2 · 2017: 4 · 2016: 10 · 2015: 2 · 2014: 5 · 2013: 6
- FWCI
- 1.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (5r01ag024379-15)
- National Institute on Aging (R01-AG024379)
- National Institute of Allergy and Infectious Diseases (P30AI050410)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Emergency Medicine › HIV-related health complications and treatments
- Keywords
- p16INK4a, T cell senescence, cellular senescence, HIV infection, antiretroviral therapy, biomarkers, CD4 count recovery, viral suppression, CD4+ T cells
- MeSH terms
- Age Factors, Humans, T-Lymphocytes, Biomarkers, HIV Infections, Case-Control Studies, Viral Load, Cyclin-Dependent Kinase Inhibitor p16, Anti-Retroviral Agents
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