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

Authors

Andrew M. Gross, University of California, San Diego
Philipp A. Jaeger, University of California, San Diego
Jason F. Kreisberg, University of California, San DiegoFollow
Katherine Licon, University of California, San Diego
Kristen L. Jepsen, University of California, San Diego
Mahdieh Khosroheidari, University of California, San Diego
Brenda M. Morsey, UNMCFollow
Susan Swindells, UNMCFollow
Hui Shen, University of California, San Diego
Cherie T. Ng, aTyr Pharmaceuticals
Ken Flagg, University of California, San Diego
Daniel Chen, University of California, San Diego
Kang Zhang, University of California, San Diego
Howard S. Fox, University of Nebraska Medical CenterFollow
Trey Ideker, University of California, San DiegoFollow

Date of this Version

2016

Document Type

Article

Citation

Molecular Cell 62, 157–168, April 21, 2016

Comments

Copyright 2016 Elsevier Inc.

This document is a U.S. government work and is not subject to copyright in the United States.

http://dx.doi.org/10.1016/j.molcel.2016.03.019

Abstract

HIV-infected individuals are living longer on antiretro-viral 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/CD8T cell ratio, linking molecular aging, epigenetic regulation, and disease progression.