Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA

Andrew M Gross; Philipp A Jaeger; Jason F Kreisberg; Katherine Licon; Kristen L Jepsen; Mahdieh Khosroheidari; Brenda M Morsey; Susan Swindells; Hui Shen; Cherie T Ng; Ken Flagg; Daniel Chen; Kang Zhang; Howard S Fox; Trey Ideker

doi:10.1016/j.molcel.2016.03.019

Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA

Mol Cell. 2016 Apr 21;62(2):157-168. doi: 10.1016/j.molcel.2016.03.019.

Authors

Affiliations

¹ Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
² Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
³ Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁵ Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁶ Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁷ aTyr Pharmaceuticals, San Diego, CA 92121, USA.
⁸ Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Guangzhou Kang Rui Biological Pharmaceutical Technology Company Ltd., Guangzhou 510005, China.
⁹ Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁰ Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Veterans Administration Healthcare System, San Diego, CA 92093, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
¹¹ Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: [email protected].
¹² Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].

Abstract

HIV-infected individuals are living longer on antiretroviral therapy, but many patients display signs that in some ways resemble premature aging. To investigate and quantify the impact of chronic HIV infection on aging, we report a global analysis of the whole-blood DNA methylomes of 137 HIV+ individuals under sustained therapy along with 44 matched HIV- individuals. First, we develop and validate epigenetic models of aging that are independent of blood cell composition. Using these models, we find that both chronic and recent HIV infection lead to an average aging advancement of 4.9 years, increasing expected mortality risk by 19%. In addition, sustained infection results in global deregulation of the methylome across >80,000 CpGs and specific hypomethylation of the region encoding the human leukocyte antigen locus (HLA). We find that decreased HLA methylation is predictive of lower CD4 / CD8 T cell ratio, linking molecular aging, epigenetic regulation, and disease progression.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics*
Aging / immunology
Anti-HIV Agents / therapeutic use
CD4-CD8 Ratio
Case-Control Studies
Chronic Disease
CpG Islands
DNA Methylation*
Disease Progression
Epigenesis, Genetic*
Gene Expression Profiling
Genome-Wide Association Study
Genotype
HIV Infections / diagnosis
HIV Infections / drug therapy
HIV Infections / genetics*
HIV Infections / immunology
HIV Infections / mortality
HLA Antigens / genetics*
HLA Antigens / immunology
Humans
Models, Genetic
Phenotype
Risk Factors
Time Factors
Treatment Outcome

Substances

Anti-HIV Agents
HLA Antigens

Abstract

Publication types

MeSH terms

Substances

Grants and funding