Top

Published in:

Open Access 13-05-2023 | Human Immunodeficiency Virus

Persistent accelerated epigenetic ageing in a longitudinal cohort of vertically infected HIV-positive adolescents

Authors: Sarah J. Heany, Andrew J. Levine, Maia Lesosky, Nicole Phillips, Jean-Paul Fouche, Landon Myer, Heather J. Zar, Dan J. Stein, Steve Horvath, Jacqueline Hoare

Published in: Journal of NeuroVirology | Issue 3/2023

Abstract

We have previously shown accelerated ageing in adolescents perinatally infected with HIV (PHIV +), based on discrepancies between epigenetic and chronological age. The current study examines follow-up longitudinal patterns of epigenetic ageing and the association of epigenetic ageing with cognition as well as whole brain structure changes in PHIV + and healthy controls enrolled in the Cape Town Adolescent Antiretroviral Cohort Study (CTAAC). The Illumina EPIC array was used to generate blood DNA methylation data from 60 PHIV + adolescents and 36 age-matched controls aged 9–12 years old at baseline and again at a 36-month follow-up. Epigenetic clock software estimated two measures of epigenetic age acceleration: extrinsic epigenetic accelerated ageing (EEAA) and age acceleration difference (AAD) at both time points. At follow-up, each participant completed neuropsychological testing, structural magnetic resonance imaging, and diffusion tensor imaging. At follow-up, PHIV infection remains associated with increased EEAA and AAD. Accelerated epigenetic ageing remained positively associated with viral load and negatively associated with CD4 ratio. EEAA was positively associated with whole brain grey matter volume and alterations in whole brain white matter integrity. AAD and EEAA were not associated with cognitive function within the PHIV + group. Measures of epigenetic ageing, as detected in DNA methylation patterns, remain increased in PHIV + adolescents across a 36-month period. Associations between epigenetic ageing measures, viral biomarkers, and alterations in brain micro- and macrostructure also persist at 36-month follow-up. Further study should determine if epigenetic age acceleration is associated with cognitive functional changes due to brain alterations in later life.

Aberg JA (2012) Aging, inflammation, and HIV infection. Topics in Antiviral Medicine 20(3):101PubMed

Ackermann C, Andronikou S, Saleh MG, Laughton B, Alhamud AA, van der Kouwe A, Meintjes EM (2016) Early antiretroviral therapy in HIV-infected children is associated with diffuse white matter structural abnormality and corpus callosum sparing. Am J Neuroradiol 37(12):2363–2369CrossRefPubMedPubMedCentral

Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, Irizarry RA (2014) Minfi: a flexible and comprehensive Bioconductor package for the analysis of infinium DNA methylation microarrays. Bioinformatics 30(10):1363–1369CrossRefPubMedPubMedCentral

Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, Zule W (2003) Development and validation of a brief screening version of the childhood trauma questionnaire. Child Abuse & Neglect 27(2):169–190CrossRef

Chen BH, Marioni RE, Colicino E, Peters MJ, Ward-Caviness CK, Tsai PC et al (2016) DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging 8:1844–1865CrossRefPubMedPubMedCentral

Cole JH, Underwood J, Caan MW, De Francesco D, van Zoest RA, Leech R, Sharp DJ (2017) Increased brain-predicted aging in treated HIV disease. Neurology 88(14):1349–1357CrossRefPubMedPubMedCentral

Desikan RS, Segonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D et al (2006) An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 31(3):968–980CrossRefPubMed

Dugue PA, Bassett JK, Joo JE, Jung CH, Ming Wong E, Moreno-Betancur M, Schmidt D, Makalic E, Li S, Severi G, Hodge AM, Buchanan DD, English DR et al (2018) DNA methylation-based biological aging and cancer risk and survival: pooled analysis of seven prospective studies. Int J Cancer 142:1611–1619. https://doi.org/10.1002/ijc.31189CrossRefPubMed

Fischl B, Dale AM (2000) Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci 97(20):11050–11055CrossRefPubMedPubMedCentral

Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C et al (2002) Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 33(3):341–355CrossRefPubMed

Gosling AS, Burns J, Hirst F (2004) Children with HIV in the UK: a longitudinal study of adaptive and cognitive functioning. Clin Child Psychol Psychiatry 9(1):25–37CrossRef

Gross AM, Jaeger PA, Kreisberg JF, Licon K, Jepsen KL, Khosroheidari M, Flagg K (2016) Methylome-wide analysis of chronic HIV infection reveals five-year increase in biological age and epigenetic targeting of HLA. Mole Cell 62(2):157–168

Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, Klotzle B, Bibikova M, Fan JB, Gao Y, Deconde R, Chen M, Rajapakse I et al (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49:359–367. https://doi.org/10.1016/j.molcel.2012.10.016CrossRefPubMed

Heany SJ, Phillips N, Brooks S, Fouche JP, Myer L, Zar H, Hoare J (2020) Neural correlates of maintenance working memory, as well as relevant structural qualities, are associated with earlier antiretroviral treatment initiation in vertically transmitted HIV. J Neurovirol 26(1):60–69

Hoare J, Fouche JP, Phillips N, Joska JA, Donald KA, Thomas K, Stein DJ (2015a) Clinical associations of white matter damage in cART-treated HIV-positive children in South Africa. J Neurovirol 21(2):120–128CrossRefPubMed

Hoare J, Fouche JP, Phillips N, Joska JA, Paul R, Donald KA, Stein DJ (2015b) White matter micro-structural changes in ART-naive and ART-treated children and adolescents infected with HIV in South Africa. AIDS 29(14):1793–1801

Hoare J, Phillips N, Joska JA, Paul R, Donald KA, Stein DJ et al (2016) Applying the HIV-associated neurocognitive disorder diagnostic criteria to HIV-infected youth. Neurology 87:86–93CrossRefPubMedPubMedCentral

Hoare J, Fouche JP, Phillips N, Joska JA, Myer L, Zar HJ, Stein DJ (2018) Structural brain changes in perinatally HIV infected young adolescents in South Africa. AIDS 32(18):2707CrossRefPubMed

Hoare J, Stein DJ, Heany SJ, Fouche JP, Phillips N, Er S, Levine AJ (2020) Accelerated epigenetic aging in adolescents from low-income households is associated with altered development of brain structures. Meta Brain Dis 35(8):1287–1298CrossRef

Hoare J, Stein DJ, Heany SJ, Fouche JP, Horvath S, Phillips N, Er S, Myer L, Zar HJ, Levine AJ (2021) Accelerated epigenetic aging in adolescents perinatally infected with HIV is associated with altered development of brain structures. J Neurovirol 28(2):208–216CrossRefPubMedPubMedCentral

Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14:R115CrossRefPubMedPubMedCentral

Horvath S, Erhart W, Brosch M, Ammerpohl O, von Schönfels W, Ahrens M, Heits N, Bell JT, Tsai PC, Spector TD, Deloukas P, Siebert R, Sipos B et al (2014) Obesity accelerates epigenetic aging of human liver. Proc Natl Acad Sci USA 111:15538–15543. https://doi.org/10.1073/pnas.1412759111CrossRefPubMedPubMedCentral

Horvath S, Levine AJ (2015) HIV-1 infection accelerates age according to the epigenetic clock. J Infect Dis 212(10):1563–1573CrossRefPubMedPubMedCentral

Horvath S, Gurven M, Levine ME, Trumble BC, Kaplan H, Allayee H et al (2016) An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biol 17:171CrossRefPubMedPubMedCentral

Horvath S, Stein DJ, Phillips N, Heany SJ, Kobor MS, Lin DT, Hoare J (2018) Perinatally acquired HIV infection accelerates epigenetic aging in South African adolescents. AIDS 32(11):1465

IBM Corp (2021) IBM SPSS Statistics for Windows, Version 28.0. Armonk, NY: IBM Corp

Jankiewicz M, Holmes MJ, Taylor PA, Cotton MF, Laughton B, Van Der Kouwe AJ, Meintjes EM (2017) White matter abnormalities in children with HIV infection and exposure. Front Neuroanat 11:88CrossRefPubMedPubMedCentral

Kolgiri V, Patil VW (2017) Protein carbonyl content: a novel biomarker for aging in HIV/AIDS patients. Braz J Infect Dis 21(1):35–41CrossRefPubMed

Levine A, Phillips N, Heany S, Stein D, Zar H, Kobor M, Horvath S (2018) Perinatally acquired HIV infection and epigenetic age acceleration in South African adolescents. J Neuroimmune Pharmacol 13:S47–S47

Levine ME, Lu AT, Bennett DA (2015a) Horvath S. Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning. Aging (Albany NY) 7:1198–211. https://doi.org/10.18632/aging.100864

Levine ME, Hosgood HD, Chen B, Absher D, Assimes T, Horvath S (2015b) DNA methylation age of blood predicts future onset of lung cancer in the women’s health initiative. Aging (Albany NY) 7:690–700. https://doi.org/10.18632/aging.100809

Marini S, Davis KA, Soare TW, Zhu Y, Suderman MJ, Simpkin AJ, Dunn EC (2020) Adversity exposure during sensitive periods predicts accelerated epigenetic aging in children. Psychoneuroendocrinol 113:104484

Marioni RE, Shah S, McRae AF, Chen BH, Colicino E, Harris SE, Gibson J, Henders AK, Redmond P, Cox SR, Pattie A, Corley J, Murphy L et al (2015a) DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol 16:25CrossRefPubMedPubMedCentral

Marioni RE, Shah S, McRae AF, Ritchie SJ, Muniz-Terrera G, Harris SE, Gibson J, Redmond P, Cox SR, Pattie A, Corley J, Taylor A, Murphy L et al (2015b) The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936. Int J Epidemiol 44:1388–1396. https://doi.org/10.1093/ije/dyu277CrossRefPubMedPubMedCentral

Nelson KN, Hui Q, Rimland D, Xu K, Freiberg MS, Justice AC, Sun YV (2017) Identification of HIV infection-related DNA methylation sites and advanced epigenetic aging in HIV+, treatment-naive US veterans. AIDS 31(4):571CrossRefPubMed

Phillips N, Amos T, Kuo C, Hoare J, Ipser J, Thomas KG, Stein DJ (2016) HIV-associated cognitive impairment in perinatally infected children: a meta-analysis. Pediatrics 138(5):e20160893CrossRefPubMedPubMedCentral

Phillips NJ, Hoare J, Stein DJ, Myer L, Zar HJ, Thomas KG (2018) HIV-associated cognitive disorders in perinatally infected children and adolescents: a novel composite cognitive domains score. AIDS Care 30(sup1):8–16CrossRefPubMed

Ruel TD, Boivin MJ, Boal HE, Bangirana P, Charlebois E, Havlir DV et al (2012) Neurocognitive and motor deficits in HIV-infected Ugandan children with high CD4 cell counts. Clin Infect Dis 54:1001–1009CrossRefPubMedPubMedCentral

Sarma MK, Nagarajan R, Keller MA, Kumar R, Nielsen-Saines K, Michalik DE, Thomas MA (2014) Regional brain gray and white matter changes in perinatally HIV-infected adolescents. NeuroImage Clin 4:29–34CrossRefPubMed

Shiau S, Strehlau R, Wang S, Violari A, Do C, Patel F, Kuhn L (2019) Distinct epigenetic profiles in children with perinatally-acquired HIV on antiretroviral therapy. Sci Rep 9(1):1–15CrossRef

Shiau S, Brummel SS, Kennedy EM, Hermetz K, Spector SA, Williams PL, Pediatric HIV/AIDS Cohort Study (PHACS) (2021a) Longitudinal changes in epigenetic age in youth with perinatally acquired HIV and youth who are perinatally HIV-exposed uninfected. AIDS 35(5):811–819CrossRef

Shiau S, Cantos A, Ramon CV, Shen Y, Shah J, Jang G, Yin MT (2021b) Epigenetic age in young African American adults with perinatally-acquired HIV. JAIDS Journal of Acquired Immune Deficiency Syndromes 87(4):1102–1109CrossRefPubMed

Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Behrens TE (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31(4):1487–1505CrossRefPubMed

Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW (2003) Mapping cortical change across the human life span. Nat Neurosci 6(3):309–315CrossRefPubMed

Squeglia LM, Jacobus J, Tapert SF (2009) The influence of substance use on adolescent brain development. Clin EEG Neurosci 40(1):31–38CrossRefPubMedPubMedCentral

Triche TJ, Weisenberger DJ, Van Den Berg D, Laird PW, Siegmund KD (2013) Low-level processing of Illumina Infinium DNA Methylation BeadArrays. Nucleic Acids Res 41:e90–e190CrossRefPubMedPubMedCentral

Willen EJ (2006) Neurocognitive outcomes in pediatric HIV. Ment Retard Dev Disabil Res Rev 12(3):223–228CrossRefPubMed

Wolters PL, Brouwers P, Civitello L, Moss HA (1997) Receptive and expressive language function of children with symptomatic HIV infection and relationship with disease parameters: a longitudinal 24-month follow-up study. AIDS 11(9):1135–1144CrossRefPubMed

Yang CX, Schon E, Obeidat ME, Kobor MS, McEwen L, MacIsaac J, INSIGHT START study group (2020) Accelerated epigenetic aging and methylation disruptions occur in human immunodeficiency virus infection prior to antiretroviral therapy. J Infect Dis 223(10):1681–1689CrossRefPubMedCentral

Title: Persistent accelerated epigenetic ageing in a longitudinal cohort of vertically infected HIV-positive adolescents
Authors: Sarah J. Heany
Andrew J. Levine
Maia Lesosky
Nicole Phillips
Jean-Paul Fouche
Landon Myer
Heather J. Zar
Dan J. Stein
Steve Horvath
Jacqueline Hoare
Publication date: 13-05-2023
Publisher: Springer International Publishing
Keywords: Human Immunodeficiency Virus
Epigenetics
Published in: Journal of NeuroVirology / Issue 3/2023
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-023-01130-6

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Persistent accelerated epigenetic ageing in a longitudinal cohort of vertically infected HIV-positive adolescents

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2023

HIV viremia contributes to neurocognitive impairments in persons who use cocaine

Epileptic seizures associated with progressive multifocal leukoencephalopathy in HIV-infected patients in Korea

Elevated Galectin-9 across the human brain correlates with HIV neuropathology and detrimental cognitive states

Multi-functional auto-fluorescent nanogels for theranostics

Brain opportunistic infections and tumors in people living with HIV — still a challenge in efficient antiretroviral therapy era

Cognitive function and impact on driving after SARS-COV-2 infection in a man with long-standing HIV infection: a case report