Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA.
Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA.
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DOI：
10.1016/j.molcel.2016.03.019
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发表时间：
2016-04-21
期刊：
影响因子：
16
通讯作者：
Ideker T
中科院分区：
文献类型：
--
作者：
Gross AM;Jaeger PA;Kreisberg JF;Licon K;Jepsen KL;Khosroheidari M;Morsey BM;Swindells S;Shen H;Ng CT;Flagg K;Chen D;Zhang K;Fox HS;Ideker T
接受抗逆转录病毒治疗的艾滋病毒感染者寿命更长，但许多患者在某些方面表现出类似于过早衰老的迹象。为了调查和量化慢性 HIV 感染对衰老的影响，我们报告了对 137 名接受持续治疗的 HIV+ 个体以及 44 名匹配的 HIV- 个体的全血 DNA 甲基化组的全球分析。首先，我们开发并验证独立于血细胞组成的衰老表观遗传模型。利用这些模型，我们发现慢性和近期 HIV 感染都会导致平均衰老 4.9 岁，使预期死亡风险增加 19%。此外，持续感染会导致超过 80,000 个 CpG 的甲基化基因组全面失调，以及编码人类白细胞抗原基因座 (HLA) 的区域发生特异性低甲基化。我们发现 HLA 甲基化降低预示着 CD4/CD8 T 细胞比率降低，将分子衰老、表观遗传调控和疾病进展联系起来。格罗斯等人。通过分析 HIV+ 个体和匹配的 HIV- 对照的 DNA 甲基化组来研究慢性 HIV 感染的影响。利用衰老的表观遗传模型，他们观察到 HIV+ 个体在全血中显示出 4.9 岁的年龄提前，并在纯细胞样本中验证了这些结果。
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. Gross et al. investigate the impact of chronic HIV infection by profiling the DNA methylomes of HIV+ individuals and matched HIV− controls. Using epigenetic models of aging they observe that HIV+ individuals show an age advancement of 4.9 years in whole blood and validate these results in pure cell samples.