Accelerated aging with HIV begins at the time of initial HIV infection

Elizabeth Crabb Breen¹, Mary E Sehl², Roger Shih², Peter Langfelder^{3

4}, Ruibin Wang⁵, Steve Horvath^{6

7}, Jay H Bream⁸, Priya Duggal⁵, Jeremy Martinson⁹, Steven M Wolinsky¹⁰, Otoniel Martínez-Maza¹¹, Christina M Ramirez¹², Beth D Jamieson²

Affiliations

¹ Cousins Center for Psychoneuroimmunology, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
² Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
³ Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MA 21205, USA.
⁶ Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁷ Altos Labs, San Diego, CA 92121, USA.
⁸ Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Graduate Program in Immunology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
⁹ Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
¹⁰ Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
¹¹ Departments of Obstetrics & Gynecology and Microbiology, Immunology, & Molecular Genetics, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
¹² Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA.

PMID: 35880029
PMCID: PMC9308149
DOI: 10.1016/j.isci.2022.104488

Accelerated aging with HIV begins at the time of initial HIV infection

Elizabeth Crabb Breen et al. iScience. 2022.

. 2022 Jun 30;25(7):104488.

doi: 10.1016/j.isci.2022.104488. eCollection 2022 Jul 15.

Authors

Affiliations

¹ Cousins Center for Psychoneuroimmunology, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
² Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
³ Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MA 21205, USA.
⁶ Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁷ Altos Labs, San Diego, CA 92121, USA.
⁸ Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Graduate Program in Immunology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
⁹ Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
¹⁰ Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
¹¹ Departments of Obstetrics & Gynecology and Microbiology, Immunology, & Molecular Genetics, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
¹² Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA.

PMID: 35880029
PMCID: PMC9308149
DOI: 10.1016/j.isci.2022.104488

Erratum in

Erratum: Accelerated aging with HIV begins at the time of initial HIV infection.
Breen EC, Sehl ME, Shih R, Langfelder P, Wang R, Horvath S, Bream JH, Duggal P, Martinson J, Wolinsky SM, Martínez-Maza O, Ramirez CM, Jamieson BD. Breen EC, et al. iScience. 2023 Jul 14;26(8):107381. doi: 10.1016/j.isci.2023.107381. eCollection 2023 Aug 18. iScience. 2023. PMID: 37520728 Free PMC article.

Abstract

Living with HIV infection is associated with early onset of aging-related chronic conditions, sometimes described as accelerated aging. Epigenetic DNA methylation patterns can evaluate acceleration of biological age relative to chronological age. The impact of initial HIV infection on five epigenetic measures of aging was examined before and approximately 3 years after HIV infection in the same individuals (n=102). Significant epigenetic age acceleration (median 1.9-4.8 years) and estimated telomere length shortening (all p≤ 0.001) were observed from pre-to post-HIV infection, and remained significant in three epigenetic measures after controlling for T cell changes. No acceleration was seen in age- and time interval-matched HIV-uninfected controls. Changes in genome-wide co-methylation clusters were also significantly associated with initial HIV infection (p≤ 2.0 × 10^-4). These longitudinal observations clearly demonstrate an early and substantial impact of HIV infection on the epigenetic aging process, and suggest a role for HIV itself in the earlier onset of clinical aging.

Keywords: Epigenetics; Human physiology; Immunology; Virology.

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Conflict of interest statement

Peter Langfelder is a paid consultant for The Bioinformatics CRO, Inc and Quantigic Genomics, LLC. Steve Horvath is a founder of the non-profit Epigenetic Clock Development Foundation which plans to license several patents from his employer UC Regents. These patents list SH as inventor.

Figures

**Figure 1**
Multiple epigenetic measures in peripheral blood mononuclear cells (PBMC) demonstrate significant differences in biological aging after initial HIV infection, compared to age-matched HIV-uninfected persons Longitudinal PBMC samples from men before (Visit A) and after (Visit B) documented HIV infection and seroconversion (SC), and from matched (chronologic age, Hepatitis C status, and time interval) persistently HIV seronegative men (SN), were evaluated for biological aging by five different age-adjusted epigenetic measures: (A) Age Acceleration Residual (AAR), (B) Extrinsic Epigenetic Age Acceleration (EEAA), (C) Phenotypic Epigenetic Age Acceleration (PEAA), (D) Grim Epigenetic Age Acceleration (GEAA), and (E) age-adjusted DNA methylation-based estimate of telomere length (aaDNAmTL) (see also Table S1). The first four are epigenetic “clocks” which increase with aging whereas estimated TL shortens (decreases) with aging. Each panel shows box and whisker plots (heavy line = median, box = 25^th-75^th percentile, whiskers = 5^th-95^th percentile) for SC (yellow) and SN (blue) participants at Visit A and Visit B; p values are for comparison of SN vs. SC at each visit by t-tests. 102 matched SC/SN pairs were evaluated; one SN participant was missing a PBMC sample at Visit A.

**Figure 2**
Significant accelerations in multiple epigenetic measures of aging occur in men over the course of initial HIV infection, but not in matched men who remain HIV-uninfected Dot plots of HIV seroconverter (SC, n = 102) and persistently HIV seronegative (SN, n = 101) participants show the epigenetic change from the pre-HIV infection or equivalent visit (Visit A) to the post-HIV infection or equivalent visit (Visit B) within each participant as measured by (A) AAR, B) EEAA, (C) PEAA, (D) GEAA, and (E) aaDNAmTL. Heavy bar and numerical value = median change, whiskers = 25^th-75^th percentiles, p values = t-test for change within each participant group for differences from zero.

See this image and copyright information in PMC

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Accelerated aging with HIV begins at the time of initial HIV infection

Affiliations

Accelerated aging with HIV begins at the time of initial HIV infection

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

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