Corneal Endothelial Cells Provide Evidence of Accelerated Cellular Senescence Associated with HIV Infection: A Case-Control Study

Sophia Pathai,Colin Cook,Helen A. Weiss,Stephen D. Lawn,Clare E. Gilbert,Robin Wood,Paul G. Shiels,Yingfeng Zheng

doi:10.1371/journal.pone.0057422

Abstract

BackgroundCellular senescence may be a key factor in HIV-related premature biological aging. We assessed features of the corneal endothelium that are known to be associated with biological aging, and cellular senescence markers in HIV-infected adults.MethodsCase-control study of 242 HIV-infected adults and 249 matched controls. Using specular microscopy, the corneal endothelium was assessed for features of aging (low endothelial cell density [ECD], high variation in cell size, and low hexagonality index). Data were analysed by multivariable regression. CDKN2A expression (a cell senescence mediator) was measured in peripheral blood leukocytes and 8-hydroxy-2′-deoxyguanosine (8-OHDG; an oxidative DNA damage marker) levels were measured in plasma.ResultsThe median age of both groups was 40 years. Among HIV-infected adults, 88% were receiving antiretroviral therapy (ART); their median CD4 count was 468 cells/µL. HIV infection was associated with increased odds of variation in cell size (OR = 1.67; 95% CI: 1.00–2.78, p = 0.04). Among HIV-infected participants, low ECD was independently associated with current CD4 count <200 cells/µL (OR = 2.77; 95%CI: 1.12–6.81, p = 0.03). In participants on ART with undetectable viral load, CDKN2A expression and 8-OHDG levels were higher in those with accelerated aging, as reflected by lower ECD.ConclusionsThe corneal endothelium shows features consistent with HIV-related accelerated senescence, especially among those with poor immune recovery.

Highlights

Patients receiving antiretroviral therapy (ART) are at increased risk of age-related non-AIDS morbidity and mortality compared with HIV-seronegative persons [1,2]
Human corneal endothelial cells (HCEC) do not have substantial replicative potential in vivo and their form and quantity influence the health of the cornea [5]
We report on the cellular aspects of aging within this study cohort, using corneal endothelial cells as readily accessible model of cellular senescence

Summary

Introduction

Patients receiving antiretroviral therapy (ART) are at increased risk of age-related non-AIDS morbidity and mortality compared with HIV-seronegative persons [1,2]. It is speculated that as those with HIV age chronologically, they are likely to undergo accelerated biological aging, mediated by increased cellular senescence. This may be due to replicative senescence (a state of irreversible cellular growth arrest) and stress-induced premature senescence (SIPS) from exposure to environmental stresses, including oxidative stress [3]. The eye may be a useful site for investigating cellular dynamics of aging, as the corneal endothelium can be readily visualized using non-invasive techniques. Cellular senescence may be a key factor in HIV-related premature biological aging. We assessed features of the corneal endothelium that are known to be associated with biological aging, and cellular senescence markers in HIV-infected adults

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