Epigenome-wide differential DNA methylation between HIV-infected and uninfected individuals.
Epigenetic control of human immunodeficiency virus-1 (HIV-1) genes is critical for viral integration and latency. However, epigenetic changes in the HIV-1-infected host genome have not been well characterized. Here, we report the first large-scale epigenome-wide association study of DNA methylation for HIV-1 infection. We recruited HIV-infected (n = 261) and uninfected (n = 117) patients from the Veteran Aging Cohort Study (VACS) and all samples were profiled for 485,521 CpG sites in DNA extracted from the blood. After adjusting for cell type and clinical confounders, we identified 20 epigenome-wide significant CpGs for HIV-1 infection. Importantly, 2 CpGs in the promoter of the NLR family, CARD domain containing gene 5 (NLRC5), a key regulator of major histocompatibility complex class I gene expression, showed significantly lower methylation in HIV-infected subjects than in uninfected subjects (cg07839457: t = -6.03, Pnominal= 4.96 × 10-9; cg16411857: t = -7.63, Pnominal= 3.07 × 10-13). Hypomethylation of these 2 CpGs was replicated in an independent sample (GSE67705: cg07839457: t = -4.44, Pnominal= 1.61 × 10-5; cg16411857: t = -5.90; P = 1.99 × 10-8). Methylation of these 2 CpGs in NLRC5 was negatively correlated with viral load in the 2 HIV-infected samples (cg07839457: P = 1.8 × 10-4; cg16411857: P = 0.03 in the VACS; and cg07839457: P = 0.04; cg164111857: P = 0.01 in GSE53840). Our findings demonstrate that differential DNA methylation is associated with HIV infection and suggest the involvement of a novel host gene, NLRC5, in HIV pathogenesis.
a Department of Psychiatry , Yale School of Medicine , New Haven , CT , USA.|b Connecticut Veteran Health System , West Haven , CT , USA.
Xinyu
X
Zhang
c Yale University School of Medicine, New Haven Veterans Affairs Connecticut Healthcare System , West Haven , CT , USA.
Amy C
AC
Justice
d Center for Biomedical Informatics & Information Technology, National Cancer Institute , Bethesda , MD , USA.
Ying
Y
Hu
e Department of Internal Medicine , Division of Infectious Disease, Yale University School of Medicine , New Haven , CT , USA.
Zuoheng
Z
Wang
f Department of Biostatistics , Yale School of Public Health , New Haven , CT , USA.
Hongyu
H
Zhao
g Yale Center of Genomic Analysis, West Campus , Orange , CT , USA.
Guilin
G
Wang
h Fellow Program and Behavioral Health and Criminal Justice Division, RTI International , Research Triangle Park, NC , USA.
Eric O
EO
Johnson
e Department of Internal Medicine , Division of Infectious Disease, Yale University School of Medicine , New Haven , CT , USA.
Brinda
B
Emu
e Department of Internal Medicine , Division of Infectious Disease, Yale University School of Medicine , New Haven , CT , USA.
Richard E
RE
Sutton
a Department of Psychiatry , Yale School of Medicine , New Haven , CT , USA.|b Connecticut Veteran Health System , West Haven , CT , USA.
John H
JH
Krystal
a Department of Psychiatry , Yale School of Medicine , New Haven , CT , USA.|b Connecticut Veteran Health System , West Haven , CT , USA.
Ke
K
Xu
DNA methylation; Epigenome-wide association; HIV-1 infection; viral load
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