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

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

doi:10.1016/j.molcel.2016.03.019

Cited by 258 publications

(251 citation statements)

References 64 publications

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“…Gross et al have demonstrated that HIV-infected individuals on sustained antiretroviral therapy have an epigenetic age about 5 years older than healthy controls. 18 Smith et al proposed that in addition to inflammation caused by HIV, adverse effects of antiretroviral drugs, specifically those that affect the mitochondria, also contribute to the accelerated aging of treated HIV-infected patients. 19 Viruses other than HIV, namely CMV and HSV, also appear to correlate with premature immune aging 5 .…”

Section: Pathophysiologic Factors Influencing Infection Risk and Pmentioning

confidence: 99%

Influence of Aging and Environment on Presentation of Infection in Older Adults

Chakhtoura

Bonomo

Jump

2017

Infectious Disease Clinics of North America

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Synopsis In older adults, pathophysiologic, clinical, and environmental factors all affect the presentation of infections. We explore how age-related changes influence the manifestation and evaluation of infections in this population. Specific topics include immunosenescence, age related organ-specific physiologic changes, and frailty. We also describe clinical factors influencing infection risk and presentation in older adults including temperature regulation, cognitive decline, and malnutrition. Finally, we discuss the influence of the setting in which older adults reside on the clinical evaluation of infection. Understanding the influence of all these changes may facilitate the prevention, early recognition and treatment of infections in older adults.

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Section: Pathophysiologic Factors Influencing Infection Risk and Pmentioning

confidence: 99%

Influence of Aging and Environment on Presentation of Infection in Older Adults

Chakhtoura

Bonomo

Jump

2017

Infectious Disease Clinics of North America

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“…A previous study reported that CpGs in the IL2 promoter were completely methylated in naïve CD4 + T cells and significantly demethylated in memory CD4 + T cells during chronic HIV infection, 14 indicating that alterations in DNA methylation occur in different subpopulations of CD4 + T cells during HIV infection. Interestingly, a recent study revealed hypomethylation in the region encoding the human leukocyte antigen locus in chronic HIV-infected patients 15 . These findings indicate that methylation should be examined at the epigenome level.…”

Section: Introductionmentioning

confidence: 96%

Epigenome-wide differential DNA methylation between HIV-infected and uninfected individuals

Zhang

Justice

et al. 2016

Epigenetics

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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.

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“…Despite virologic control of HIV, individuals on cART are susceptible to aging-associated diseases such as cardiovascular disease, kidney disease, neurocognitive decline, and cancer at earlier ages (1), suggesting premature aging in this population. Epigenetic modeling studies on blood cells have shown that cART-treated HIV-infected individuals display an approximately 5-year age acceleration compared with healthy controls (2,3). Correlates of non-AIDS morbidity and mortality in cART-treated HIV + individuals include markers of innate and adaptive immune activation (IA) and inflammation, which can persist despite cART-induced recovery of CD4 + T cell counts (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%