Effects of highly active antiretroviral therapy initiation on epigenomic DNA methylation in persons living with HIV

Joshua Zhang; Mary E. Sehl; Roger Shih; Elizabeth Crabb Breen; Fengxue Li; Ake T. Lu; Jay H. Bream; Priya Duggal; Jeremy Martinson; Steven M. Wolinsky; Otoniel Martinez-Maza; Christina M. Ramirez; Steve Horvath; Beth D. Jamieson

doi:10.3389/fbinf.2024.1357889

Effects of highly active antiretroviral therapy initiation on epigenomic DNA methylation in persons living with HIV

Joshua Zhang, Mary E. Sehl, Roger Shih, Elizabeth Crabb Breen, Fengxue Li, Ake T. Lu, Jay H. Bream, Priya Duggal, Jeremy Martinson, Steven M. Wolinsky, Otoniel Martinez-Maza, Christina M. Ramirez, Steve Horvath, Beth D. Jamieson^*

^*Corresponding author for this work

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

Abstract

Introduction: Highly active antiretroviral therapy (HAART) helps improve some measures of accelerated epigenetic aging in persons living with HIV (PLWH), but its overall impact on the epigenome is not fully understood. Methods: In this study, we analyzed the DNA methylation profiles of PLWH (n = 187) shortly before and approximately 2–3 years after they started HAART, as well as matched seronegative (SN) controls (n = 187), taken at two time intervals. Our aim was to identify specific CpGs and biologic pathways associated with HIV infection and initiation of HAART. Additionally, we attempted to identify epigenetic changes associated with HAART initiation that were independent of HIV-associated changes, using matched HIV seronegative (SN) controls (matched on age, hepatitis C status, and interval between visits) to identify CpGs that did not differ between PLWH and SN pre-HAART but were significantly associated with HAART initiation while being unrelated to HIV viral load. Epigenome-wide association studies (EWAS) on >850,000 CpG sites were performed using pre- and post-HAART samples from PLWH. The results were then annotated using the Genomic Regions Enrichment of Annotations Tool (GREAT). Results: When only pre- and post-HAART visits in PLWH were compared, gene ontologies related to immune function and diseases related to immune function were significant, though with less significance for PLWH with detectable HIV viral loads (>50 copies/mL) at the post-HAART visit. To specifically elucidate the effects of HAART separately from HIV-induced methylation changes, we performed EWAS of HAART while also controlling for HIV viral load, and found gene ontologies associated with transplant rejection, transplant-related diseases, and other immunologic signatures. Additionally, we performed a more focused analysis that examined CpGs reaching genome-wide significance (p < 1 × 10⁻⁷) from the viral load-controlled EWAS that did not differ between all PLWH and matched SN controls pre-HAART. These CpGs were found to be near genes that play a role in retroviral drug metabolism, diffuse large B cell lymphoma proliferation, and gastric cancer metastasis. Discussion: Overall, this study provides insight into potential biological functions associated with DNA methylation changes induced by HAART initiation in persons living with HIV.

Original language	English (US)
Article number	1357889
Journal	Frontiers in Bioinformatics
Volume	4
DOIs	https://doi.org/10.3389/fbinf.2024.1357889
State	Published - 2024

Funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. Funding for the contributing MWCCS sites (Principal Investigators) is as follows: Baltimore CRS (Todd Brown and Joseph Margolick), U01-HL146201; Chicago-Northwestern CRS (SW, Frank Palella, and Valentina Stosor), U01-HL146240; Los Angeles CRS (Roger Detels and Matthew Mimiaga), U01-HL146333; Data Analysis and Coordination Center (Gypsyamber D\u2019Souza, Stephen Gange and Elizabeth Topper), U01-HL146193; Pittsburgh CRS (JM and Charles Rinaldo), U01-HL14620. The MWCCS is funded primarily by the National Heart, Lung, and Blood Institute (NHLBI), with additional co-funding from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development (NICHD), National Institute On Aging (NIA), National Institute Of Dental & Craniofacial Research (NIDCR), National Institute Of Allergy And Infectious Diseases (NIAID), National Institute Of Neurological Disorders And Stroke (NINDS), National Institute Of Mental Health (NIMH), National Institute On Drug Abuse (NIDA), National Institute Of Nursing Research (NINR), National Cancer Institute (NCI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute on Deafness and Other Communication Disorders (NIDCD), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute on Minority Health and Health Disparities (NIMHD), and in coordination and alignment with the research priorities of the National Institutes of Health, Office of AIDS Research (OAR). MWCCS data collection is also supported by UL1-TR000004 (UCSF CTSA), UL1-TR003098 (JHU ICTR), UL1-TR001881 (UCLA CTSI), P30-AI-050409 (Atlanta CFAR), P30-AI-073961 (Miami CFAR), P30-AI-050410 (UNC CFAR), P30-AI-027767 (UAB CFAR), P30-MH-116867 (Miami CHARM), UL1-TR001409 (DC CTSA), KL2-TR001432 (DC CTSA), and TL1-TR001431 (DC CTSA). This work was supported by grant R01 AG052340 from the NIH National Institute on Aging to BJ who is also supported by U01-HL146333, and by the Susan G. Komen Career Catalyst Award CCR16380478 to MS. CR is supported by P30 MH058107.

Keywords

DNA methylation
EWAS
HIV
antiretroviral therapy
bioinformatics
epigenetics

ASJC Scopus subject areas

Biochemistry
Biotechnology
Computational Mathematics
Statistics and Probability
Structural Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3389/fbinf.2024.1357889

Cite this

Zhang, J., Sehl, M. E., Shih, R., Breen, E. C., Li, F., Lu, A. T., Bream, J. H., Duggal, P., Martinson, J., Wolinsky, S. M., Martinez-Maza, O., Ramirez, C. M., Horvath, S., & Jamieson, B. D. (2024). Effects of highly active antiretroviral therapy initiation on epigenomic DNA methylation in persons living with HIV. Frontiers in Bioinformatics, 4, Article 1357889. https://doi.org/10.3389/fbinf.2024.1357889

@article{f278371afe64472bbda8dfe34fb909d0,

title = "Effects of highly active antiretroviral therapy initiation on epigenomic DNA methylation in persons living with HIV",

abstract = "Introduction: Highly active antiretroviral therapy (HAART) helps improve some measures of accelerated epigenetic aging in persons living with HIV (PLWH), but its overall impact on the epigenome is not fully understood. Methods: In this study, we analyzed the DNA methylation profiles of PLWH (n = 187) shortly before and approximately 2–3 years after they started HAART, as well as matched seronegative (SN) controls (n = 187), taken at two time intervals. Our aim was to identify specific CpGs and biologic pathways associated with HIV infection and initiation of HAART. Additionally, we attempted to identify epigenetic changes associated with HAART initiation that were independent of HIV-associated changes, using matched HIV seronegative (SN) controls (matched on age, hepatitis C status, and interval between visits) to identify CpGs that did not differ between PLWH and SN pre-HAART but were significantly associated with HAART initiation while being unrelated to HIV viral load. Epigenome-wide association studies (EWAS) on >850,000 CpG sites were performed using pre- and post-HAART samples from PLWH. The results were then annotated using the Genomic Regions Enrichment of Annotations Tool (GREAT). Results: When only pre- and post-HAART visits in PLWH were compared, gene ontologies related to immune function and diseases related to immune function were significant, though with less significance for PLWH with detectable HIV viral loads (>50 copies/mL) at the post-HAART visit. To specifically elucidate the effects of HAART separately from HIV-induced methylation changes, we performed EWAS of HAART while also controlling for HIV viral load, and found gene ontologies associated with transplant rejection, transplant-related diseases, and other immunologic signatures. Additionally, we performed a more focused analysis that examined CpGs reaching genome-wide significance (p < 1 × 10−7) from the viral load-controlled EWAS that did not differ between all PLWH and matched SN controls pre-HAART. These CpGs were found to be near genes that play a role in retroviral drug metabolism, diffuse large B cell lymphoma proliferation, and gastric cancer metastasis. Discussion: Overall, this study provides insight into potential biological functions associated with DNA methylation changes induced by HAART initiation in persons living with HIV.",

keywords = "DNA methylation, EWAS, HIV, antiretroviral therapy, bioinformatics, epigenetics",

author = "Joshua Zhang and Sehl, {Mary E.} and Roger Shih and Breen, {Elizabeth Crabb} and Fengxue Li and Lu, {Ake T.} and Bream, {Jay H.} and Priya Duggal and Jeremy Martinson and Wolinsky, {Steven M.} and Otoniel Martinez-Maza and Ramirez, {Christina M.} and Steve Horvath and Jamieson, {Beth D.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2024 Zhang, Sehl, Shih, Breen, Li, Lu, Bream, Duggal, Martinson, Wolinsky, Martinez-Maza, Ramirez, Horvath and Jamieson.",

year = "2024",

doi = "10.3389/fbinf.2024.1357889",

language = "English (US)",

volume = "4",

journal = "Frontiers in Bioinformatics",

issn = "2673-7647",

publisher = "Frontiers Media SA",

}

Zhang, J, Sehl, ME, Shih, R, Breen, EC, Li, F, Lu, AT, Bream, JH, Duggal, P, Martinson, J, Wolinsky, SM, Martinez-Maza, O, Ramirez, CM, Horvath, S & Jamieson, BD 2024, 'Effects of highly active antiretroviral therapy initiation on epigenomic DNA methylation in persons living with HIV', Frontiers in Bioinformatics, vol. 4, 1357889. https://doi.org/10.3389/fbinf.2024.1357889

TY - JOUR

T1 - Effects of highly active antiretroviral therapy initiation on epigenomic DNA methylation in persons living with HIV

AU - Zhang, Joshua

AU - Sehl, Mary E.

AU - Shih, Roger

AU - Breen, Elizabeth Crabb

AU - Li, Fengxue

AU - Lu, Ake T.

AU - Bream, Jay H.

AU - Duggal, Priya

AU - Martinson, Jeremy

AU - Wolinsky, Steven M.

AU - Martinez-Maza, Otoniel

AU - Ramirez, Christina M.

AU - Horvath, Steve

AU - Jamieson, Beth D.

PY - 2024

Y1 - 2024

N2 - Introduction: Highly active antiretroviral therapy (HAART) helps improve some measures of accelerated epigenetic aging in persons living with HIV (PLWH), but its overall impact on the epigenome is not fully understood. Methods: In this study, we analyzed the DNA methylation profiles of PLWH (n = 187) shortly before and approximately 2–3 years after they started HAART, as well as matched seronegative (SN) controls (n = 187), taken at two time intervals. Our aim was to identify specific CpGs and biologic pathways associated with HIV infection and initiation of HAART. Additionally, we attempted to identify epigenetic changes associated with HAART initiation that were independent of HIV-associated changes, using matched HIV seronegative (SN) controls (matched on age, hepatitis C status, and interval between visits) to identify CpGs that did not differ between PLWH and SN pre-HAART but were significantly associated with HAART initiation while being unrelated to HIV viral load. Epigenome-wide association studies (EWAS) on >850,000 CpG sites were performed using pre- and post-HAART samples from PLWH. The results were then annotated using the Genomic Regions Enrichment of Annotations Tool (GREAT). Results: When only pre- and post-HAART visits in PLWH were compared, gene ontologies related to immune function and diseases related to immune function were significant, though with less significance for PLWH with detectable HIV viral loads (>50 copies/mL) at the post-HAART visit. To specifically elucidate the effects of HAART separately from HIV-induced methylation changes, we performed EWAS of HAART while also controlling for HIV viral load, and found gene ontologies associated with transplant rejection, transplant-related diseases, and other immunologic signatures. Additionally, we performed a more focused analysis that examined CpGs reaching genome-wide significance (p < 1 × 10−7) from the viral load-controlled EWAS that did not differ between all PLWH and matched SN controls pre-HAART. These CpGs were found to be near genes that play a role in retroviral drug metabolism, diffuse large B cell lymphoma proliferation, and gastric cancer metastasis. Discussion: Overall, this study provides insight into potential biological functions associated with DNA methylation changes induced by HAART initiation in persons living with HIV.

AB - Introduction: Highly active antiretroviral therapy (HAART) helps improve some measures of accelerated epigenetic aging in persons living with HIV (PLWH), but its overall impact on the epigenome is not fully understood. Methods: In this study, we analyzed the DNA methylation profiles of PLWH (n = 187) shortly before and approximately 2–3 years after they started HAART, as well as matched seronegative (SN) controls (n = 187), taken at two time intervals. Our aim was to identify specific CpGs and biologic pathways associated with HIV infection and initiation of HAART. Additionally, we attempted to identify epigenetic changes associated with HAART initiation that were independent of HIV-associated changes, using matched HIV seronegative (SN) controls (matched on age, hepatitis C status, and interval between visits) to identify CpGs that did not differ between PLWH and SN pre-HAART but were significantly associated with HAART initiation while being unrelated to HIV viral load. Epigenome-wide association studies (EWAS) on >850,000 CpG sites were performed using pre- and post-HAART samples from PLWH. The results were then annotated using the Genomic Regions Enrichment of Annotations Tool (GREAT). Results: When only pre- and post-HAART visits in PLWH were compared, gene ontologies related to immune function and diseases related to immune function were significant, though with less significance for PLWH with detectable HIV viral loads (>50 copies/mL) at the post-HAART visit. To specifically elucidate the effects of HAART separately from HIV-induced methylation changes, we performed EWAS of HAART while also controlling for HIV viral load, and found gene ontologies associated with transplant rejection, transplant-related diseases, and other immunologic signatures. Additionally, we performed a more focused analysis that examined CpGs reaching genome-wide significance (p < 1 × 10−7) from the viral load-controlled EWAS that did not differ between all PLWH and matched SN controls pre-HAART. These CpGs were found to be near genes that play a role in retroviral drug metabolism, diffuse large B cell lymphoma proliferation, and gastric cancer metastasis. Discussion: Overall, this study provides insight into potential biological functions associated with DNA methylation changes induced by HAART initiation in persons living with HIV.

KW - DNA methylation

KW - EWAS

KW - HIV

KW - antiretroviral therapy

KW - bioinformatics

KW - epigenetics

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UR - http://www.scopus.com/inward/citedby.url?scp=85195254080&partnerID=8YFLogxK

U2 - 10.3389/fbinf.2024.1357889

DO - 10.3389/fbinf.2024.1357889

M3 - Article

C2 - 38855142

AN - SCOPUS:85195254080

SN - 2673-7647

VL - 4

JO - Frontiers in Bioinformatics

JF - Frontiers in Bioinformatics

M1 - 1357889

ER -

Effects of highly active antiretroviral therapy initiation on epigenomic DNA methylation in persons living with HIV

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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