Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA.
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.
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.
Andrew M
AM
Gross
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Philipp A
PA
Jaeger
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Jason F
JF
Kreisberg
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Katherine
K
Licon
Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Kristen L
KL
Jepsen
Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Mahdieh
M
Khosroheidari
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Brenda M
BM
Morsey
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Susan
S
Swindells
Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Hui
H
Shen
aTyr Pharmaceuticals, San Diego, CA 92121, USA.
Cherie T
CT
Ng
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.
Ken
K
Flagg
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.
Daniel
D
Chen
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.
Kang
K
Zhang
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: hfox@unmc.edu.
Howard S
HS
Fox
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: tideker@ucsd.edu.
Trey
T
Ideker
D000375:Aging / Q000235:genetics* / Q000276:immunology; D019380:Anti-HIV Agents / Q000627:therapeutic use; D016516:CD4-CD8 Ratio; D016022:Case-Control Studies; D002908:Chronic Disease; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D005838:Genotype; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008957:Models, Genetic; D010641:Phenotype; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D006680:HLA Antigens