The Effects of Anti-retroviral Therapy on Epigenetic Age Acceleration Observed in HIV-1-infected Adults

Mary E. Sehl, Tammy M. Rickabaugh, Roger Shih, Otoniel Martinez-Maza, Steve Horvath, Christina M. Ramirez, Beth D. Jamieson

Abstract


Background: HIV-1 infection is associated with acceleration of age-related methylation patterns in peripheral blood and brain of infected individuals although the relative contributions of HIV-1 infection versus its treatment to the observed accelerations in biological aging have not yet been investigated.

Methods: In this longitudinal study of the effects of antiretroviral therapy (ART) on epigenetic aging patterns, we extracted DNA from peripheral blood mononuclear cells from 15 HIV-1-infected individuals infected at three time points: 6 months-1year pre-ART, 6-12 months post-initiation of ART, and 18-24 months after initiating ART. We compared these trajectories with those of 15 age-matched uninfected control participants at three time points with similar intervals. Methylation studies were performed using the Infinium methylation 450 arrays. We examined four epigenetic clock measurements: Age acceleration residual (AAR), Extrinsic (EEAA), Phenotypic (PEAA), and Grim (GEAA) epigenetic age acceleration. Weighted correlation network (WGCNA) analysis was used to identify clusters of highly co-methylated CpGs.

Results: We found that prior to the initiation of ART all four epigenetic measures were significantly higher in HIV-1-infected individuals compared with uninfected individuals (P<0.001 for AAR, P=0.008 for EEAA, P=0.012 for GEAA, P<0.001 for PEAA using Wilcoxon rank sum tests between serostatus groups). These effects persisted after the initiation of ART, although the magnitude of these differences diminished. At 18-24 months post-ART initiation (time point 3), PEAA and GEAA were no longer significantly different between HIV-1-infected and uninfected individuals (P=0.059 for PEAA, P=0.11 for GEAA), while AAR and EEAA remained significantly higher in HIV-1-infected individuals compared with uninfected individuals. We further examined for global patterns of methylation differences between HIV-1-infected and uninfected at each time point, and found 14 groups of co-methylated CpGs that were significantly different between groups at baseline, and remained different after the initiation of ART.

Conclusion: We confirm that epigenetic age acceleration associated with HIV-1 infection is most dramatic before ART initiation, and this observation is consistent across four epigenetic clock measurements, as well as in additional groups of co-methylated CpGs identified using WGCNA. Following initiation of ART, there is a partial reduction in age acceleration in all measures, with loss of any significant difference in PEAA and GEAA between serostatus groups. Our findings support the need for future studies examining for a link between epigenetic age acceleration and clinical outcomes in HIV-1-infected individuals.


Keywords


HIV, aging, methylation, epigenetics, epigenetic clock

Full Text:

HTML PDF

References


1. Schrack JA, Althoff KN, Jacobson LP, Erlandson KM, Jamieson BD, Koletar SL, Phair J, Ferrucci L, Brown TT, Margolick JB, Multicenter ACS. Accelerated Longitudinal Gait Speed Decline in HIV-Infected Older Men. J Acquir Immune Defic Syndr. 2015;70(4):370-6. Epub 2015/06/24. doi: 10.1097/QAI.0000000000000731. PubMed PMID: 26102450; PMCID: PMC4624470.

2. Schrack JA, Jacobson LP, Althoff KN, Erlandson KM, Jamieson BD, Koletar SL, Phair J, Brown TT, Margolick JB, Multicenter ACS. Effect of HIV-infection and cumulative viral load on age-related decline in grip strength. AIDS. 2016;30(17):2645-52. Epub 2016/10/27. doi: 10.1097/QAD.0000000000001245. PubMed PMID: 27603294; PMCID: PMC5083134.

3. Cole JH, Underwood J, Caan MW, De Francesco D, van Zoest RA, Leech R, Wit FW, Portegies P, Geurtsen GJ, Schmand BA, Schim van der Loeff MF, Franceschi C, Sabin CA, Majoie CB, Winston A, Reiss P, Sharp DJ, collaboration C. Increased brain-predicted aging in treated HIV disease. Neurology. 2017;88(14):1349-57. Epub 2017/03/05. doi: 10.1212/WNL.0000000000003790. PubMed PMID: 28258081; PMCID: PMC5379929.

4. High KP, Brennan-Ing M, Clifford DB, Cohen MH, Currier J, Deeks SG, Deren S, Effros RB, Gebo K, Goronzy JJ, Justice AC, Landay A, Levin J, Miotti PG, Munk RJ, Nass H, Rinaldo CR, Jr., Shlipak MG, Tracy R, Valcour V, Vance DE, Walston JD, Volberding P, HIV OARWGo, Aging. HIV and aging: state of knowledge and areas of critical need for research. A report to the NIH Office of AIDS Research by the HIV and Aging Working Group. J Acquir Immune Defic Syndr. 2012;60 Suppl 1(Suppl 1):S1-18. Epub 2012/08/08. doi: 10.1097/QAI.0b013e31825a3668. PubMed PMID: 22688010; PMCID: PMC3413877.

5. Smith RL, de Boer R, Brul S, Budovskaya Y, van Spek H. Premature and accelerated aging: HIV or HAART? Front Genet. 2012;3:328. Epub 2013/02/02. doi: 10.3389/fgene.2012.00328. PubMed PMID: 23372574; PMCID: PMC3556597.

6. Rickabaugh TM, Baxter RM, Sehl M, Sinsheimer JS, Hultin PM, Hultin LE, Quach A, Martinez-Maza O, Horvath S, Vilain E, Jamieson BD. Acceleration of age-associated methylation patterns in HIV-1-infected adults. PLoS One. 2015;10(3):e0119201. Epub 2015/03/26. doi: 10.1371/journal.pone.0119201. PubMed PMID: 25807146; PMCID: PMC4373843.

7. Horvath S, Levine AJ. HIV-1 Infection Accelerates Age According to the Epigenetic Clock. J Infect Dis. 2015;212(10):1563-73. Epub 2015/05/15. doi: 10.1093/infdis/jiv277. PubMed PMID: 25969563; PMCID: PMC4621253.

8. Gross AM, Jaeger PA, Kreisberg JF, Licon K, Jepsen KL, Khosroheidari M, Morsey BM, Swindells S, Shen H, Ng CT, Flagg K, Chen D, Zhang K, Fox HS, Ideker T. Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA. Mol Cell. 2016;62(2):157-68. Epub 2016/04/23. doi: 10.1016/j.molcel.2016.03.019. PubMed PMID: 27105112; PMCID: PMC4995115.

9. Horvath S, Stein DJ, Phillips N, Heany SJ, Kobor MS, Lin DTS, Myer L, Zar HJ, Levine AJ, Hoare J. Perinatally acquired HIV infection accelerates epigenetic aging in South African adolescents. AIDS. 2018;32(11):1465-74. Epub 2018/05/11. doi: 10.1097/QAD.0000000000001854. PubMed PMID: 29746298; PMCID: PMC6026068.

10. Kaslow RA, Ostrow DG, Detels R, Phair JP, Polk BF, Rinaldo CR, Jr. The Multicenter AIDS Cohort Study: rationale, organization, and selected characteristics of the participants. Am J Epidemiol. 1987;126(2):310-8. Epub 1987/08/01. doi: 10.1093/aje/126.2.310. PubMed PMID: 3300281.

11. Troyanskaya O, Cantor M, Sherlock G, Brown P, Hastie T, Tibshirani R, Botstein D, Altman RB. Missing value estimation methods for DNA microarrays. Bioinformatics. 2001;17(6):520-5. Epub 2001/06/08. doi: 10.1093/bioinformatics/17.6.520. PubMed PMID: 11395428.

12. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559. Epub 2008/12/31. doi: 10.1186/1471-2105-9-559. PubMed PMID: 19114008; PMCID: PMC2631488.

13. van Eijk KR, de Jong S, Boks MP, Langeveld T, Colas F, Veldink JH, de Kovel CG, Janson E, Strengman E, Langfelder P, Kahn RS, van den Berg LH, Horvath S, Ophoff RA. Genetic analysis of DNA methylation and gene expression levels in whole blood of healthy human subjects. BMC Genomics. 2012;13:636. Epub 2012/11/20. doi: 10.1186/1471-2164-13-636. PubMed PMID: 23157493; PMCID: PMC3583143.

14. Yip AM, Horvath S. Gene network interconnectedness and the generalized topological overlap measure. BMC Bioinformatics. 2007;8:22. Epub 2007/01/26. doi: 10.1186/1471-2105-8-22. PubMed PMID: 17250769; PMCID: PMC1797055.

15. Song L, Langfelder P, Horvath S. Comparison of co-expression measures: mutual information, correlation, and model based indices. BMC Bioinformatics. 2012;13:328. Epub 2012/12/12. doi: 10.1186/1471-2105-13-328. PubMed PMID: 23217028; PMCID: PMC3586947.

16. Horvath S, Dong J. Geometric interpretation of gene coexpression network analysis. PLoS Comput Biol. 2008;4(8):e1000117. Epub 2008/08/16. doi: 10.1371/journal.pcbi.1000117. PubMed PMID: 18704157; PMCID: PMC2446438.

17. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115. Epub 2013/10/22. doi: 10.1186/gb-2013-14-10-r115. PubMed PMID: 24138928; PMCID: PMC4015143.

18. Chen BH, Marioni RE, Colicino E, Peters MJ, Ward-Caviness CK, Tsai PC, Roetker NS, Just AC, Demerath EW, Guan W, Bressler J, Fornage M, Studenski S, Vandiver AR, Moore AZ, Tanaka T, Kiel DP, Liang L, Vokonas P, Schwartz J, Lunetta KL, Murabito JM, Bandinelli S, Hernandez DG, Melzer D, Nalls M, Pilling LC, Price TR, Singleton AB, Gieger C, Holle R, Kretschmer A, Kronenberg F, Kunze S, Linseisen J, Meisinger C, Rathmann W, Waldenberger M, Visscher PM, Shah S, Wray NR, McRae AF, Franco OH, Hofman A, Uitterlinden AG, Absher D, Assimes T, Levine ME, Lu AT, Tsao PS, Hou L, Manson JE, Carty CL, LaCroix AZ, Reiner AP, Spector TD, Feinberg AP, Levy D, Baccarelli A, van Meurs J, Bell JT, Peters A, Deary IJ, Pankow JS, Ferrucci L, Horvath S. DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging (Albany NY). 2016;8(9):1844-65. Epub 2016/10/01. doi: 10.18632/aging.101020. PubMed PMID: 27690265; PMCID: PMC5076441.

19. 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, Friend S, Ideker T, Zhang K. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013;49(2):359-67. Epub 2012/11/28. doi: 10.1016/j.molcel.2012.10.016. PubMed PMID: 23177740; PMCID: PMC3780611.

20. Levine ME, Lu AT, Quach A, Chen BH, Assimes TL, Bandinelli S, Hou L, Baccarelli AA, Stewart JD, Li Y, Whitsel EA, Wilson JG, Reiner AP, Aviv A, Lohman K, Liu Y, Ferrucci L, Horvath S. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY). 2018;10(4):573-91. Epub 2018/04/21. doi: 10.18632/aging.101414. PubMed PMID: 29676998; PMCID: PMC5940111.

21. Lu AT, Quach A, Wilson JG, Reiner AP, Aviv A, Raj K, Hou L, Baccarelli AA, Li Y, Stewart JD, Whitsel EA, Assimes TL, Ferrucci L, Horvath S. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY). 2019;11(2):303-27. Epub 2019/01/23. doi: 10.18632/aging.101684. PubMed PMID: 30669119; PMCID: PMC6366976.

22. Aloia L, Di Stefano B, Di Croce L. Polycomb complexes in stem cells and embryonic development. Development. 2013;140(12):2525-34. Epub 2013/05/30. doi: 10.1242/dev.091553. PubMed PMID: 23715546.

23. Guaraldi G, De Francesco D, Milic J, Franconi I, Mussini C, Falutz J, Cesari M. The Interplay Between Age and Frailty in People Living With HIV: Results From an 11-Year Follow-up Observational Study. Open Forum Infect Dis. 2019;6(5):ofz199. Epub 2019/05/28. doi: 10.1093/ofid/ofz199. PubMed PMID: 31123697; PMCID: PMC6524826.

24. Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, Berti A, Rossi E, Roverato A, Palella F. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis. 2011;53(11):1120-6. Epub 2011/10/15. doi: 10.1093/cid/cir627. PubMed PMID: 21998278.

25. Greene M, Covinsky KE, Valcour V, Miao Y, Madamba J, Lampiris H, Cenzer IS, Martin J, Deeks SG. Geriatric Syndromes in Older HIV-Infected Adults. J Acquir Immune Defic Syndr. 2015;69(2):161-7. Epub 2015/05/27. doi: 10.1097/QAI.0000000000000556. PubMed PMID: 26009828; PMCID: PMC4445476.

26. Cao W, Jamieson BD, Hultin LE, Hultin PM, Effros RB, Detels R. Premature aging of T cells is associated with faster HIV-1 disease progression. J Acquir Immune Defic Syndr. 2009;50(2):137-47. Epub 2009/01/10. doi: 10.1097/QAI.0b013e3181926c28. PubMed PMID: 19131896; PMCID: PMC2767229.

27. Dock JN, Effros RB. Role of CD8 T Cell Replicative Senescence in Human Aging and in HIV-mediated Immunosenescence. Aging Dis. 2011;2(5):382-97. Epub 2012/02/07. PubMed PMID: 22308228; PMCID: PMC3269814.

28. Cohen J, Torres C. HIV-associated cellular senescence: A contributor to accelerated aging. Ageing Res Rev. 2017;36:117-24. Epub 2016/12/27. doi: 10.1016/j.arr.2016.12.004. PubMed PMID: 28017881; PMCID: PMC5584608.


Refbacks

  • There are currently no refbacks.




Copyright (c) 2020 Mary E. Sehl

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

© Pathogens and Immunity 2019

Case Western Reserve University; Division of Infectious Diseases

10900 Euclid Ave.; Mailstop 4984; Cleveland, OH 44106

(216) 368-6317; ISSN: 2469-2964; info@paijournal.com