Abstract
Introduction: Persons living with HIV (PLWH) experience the early onset of age-related illnesses, even in the setting of successful human immunodeficiency virus (HIV) suppression with highly active antiretroviral therapy (HAART). HIV infection is associated with accelerated epigenetic aging as measured using DNA methylation (DNAm)-based estimates of biological age and of telomere length (TL). Methods: DNAm levels (Infinium MethylationEPIC BeadChip) from peripheral blood mononuclear cells from 200 PLWH and 199 HIV-seronegative (SN) participants matched on chronologic age, hepatitis C virus, and time intervals were used to calculate epigenetic age acceleration, expressed as age-adjusted acceleration residuals from 4 epigenetic clocks [Horvath’s pan-tissue age acceleration residual (AAR), extrinsic epigenetic age acceleration (EEAA), phenotypic epigenetic age acceleration (PEAA), and grim epigenetic age acceleration (GEAA)] plus age-adjusted DNAm-based TL (aaDNAmTL). Epigenetic age acceleration was compared for PLWH and SN participants at two visits: up to 1.5 years prior and 2–3 years after HAART (or equivalent visits). Flow cytometry was performed in PLWH and SN participants at both visits to evaluate T-cell subsets. Results: Epigenetic age acceleration in PLWH decreased after the initiation of HAART but remained greater post-HAART than that in age-matched SN participants, with differences in medians of 6.6, 9.1, and 7.7 years for AAR, EEAA, and PEAA, respectively, and 0.39 units of aaDNAmTL shortening (all p < 0.001). Cumulative HIV viral load after HAART initiation was associated with some epigenetic acceleration (EEAA, PEAA, and aaDNAmTL), but even PLWH with undetectable HIV post-HAART showed persistent epigenetic age acceleration compared to SN participants (p < 0.001). AAR, EEAA, and aaDNAmTL showed significant associations with total, naïve, and senescent CD8 T-cell counts; the total CD4 T-cell counts were associated with AAR, EEAA, and PEAA (p = 0.04 to <0.001). In an epigenome-wide analysis using weighted gene co-methylation network analyses, 11 modules demonstrated significant DNAm differences pre- to post-HAART initiation. Of these, nine were previously identified as significantly different from pre- to post-HIV infection but in the opposite direction. Discussion: In this large longitudinal study, we demonstrated that, although the magnitude of the difference decreases with HAART is associated with the cumulative viral load, PLWH are persistently epigenetically older than age-matched SN participants even after the successful initiation of HAART, and these changes are associated with changes in T-cell subsets.
| Original language | English (US) |
|---|---|
| Article number | 1356509 |
| Journal | Frontiers in Bioinformatics |
| Volume | 4 |
| DOIs | |
| State | Published - 2024 |
Funding
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by grant R01 AG052340 from the NIH National Institute on Aging to BJ, who was also supported by U01-HL146333, and by the Susan G. Komen Career Catalyst Award CCR16380478 to MS. CR was supported by P30 MH058107. Data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS), now the MACS/WIHS Combined Cohort Study (MWCCS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the NIH. Funding for the contributing MWCCS sites was as follows: (principal investigators): Baltimore CRS (T. Brown, J. Margolick), U01-HL146201; Data Analysis and Coordination Center (G. D\u2019Souza, S. Gange, E. Golub), U01-HL146193; Chicago\u2013Northwestern CRS (SW), U01-HL146240; Los Angeles CRS (R. Detels, M. Mimiaga), U01-HL146333; and Pittsburgh CRS (JM, C. Rinaldo), U01-HL146208. The MWCCS is funded primarily by the National Heart, Lung, and Blood Institute (NHLBI), with additional co-funding from other institutes, and in coordination and alignment with the research priorities of the NIH Office of AIDS Research (OAR). Contributing MWCCS site data collection is also supported by UL1-TR003098 (JHUICTR) and UL1-TR001881 (UCLA CTSI). Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility supported by the National Institutes of Health (NIH) awards P30 CA016042 and 5P30 AI028697, and by the JCCC, AIDS Institute, David Geffen School of Medicine, Chancellor\u2019s Office, and Vice Chancellor\u2019s Office of Research at UCLA.
Keywords
- DNA methylation
- aging
- antiretroviral therapy
- epigenetic clock
- human immunodeficiency virus
ASJC Scopus subject areas
- Biochemistry
- Biotechnology
- Computational Mathematics
- Statistics and Probability
- Structural Biology
