Distinct epigenetic profiles in children with perinatally-acquired HIV on antiretroviral therapy

Stephanie Shiau,Shuang Wang,Renate Strehlau,Avy Violari,Afaaf Liberty,Catherine Do,Faeezah Patel,Stephen M Arpadi,Louise Kuhn,Ashraf Coovadia,Elaine J Abrams,Mary Beth Terry,Benjamin Tycko,Marc Foca,Izabela Krupska

doi:10.1038/s41598-019-46930-1

Abstract

Perinatally-acquired HIV has persistent effects on long-term health outcomes, even after early treatment. We hypothesize that epigenetic indicators, such as DNA methylation, may elucidate cellular processes that explain these effects. Here, we compared DNA methylation profiles in whole blood from 120 HIV-infected children on antiretroviral therapy (ART) and 60 frequency age-matched HIV-uninfected children aged 4–9 years in Johannesburg, South Africa. Using an individual CpG site approach, we found 1,309 differentially-methylated (DM) CpG sites between groups, including 1,271 CpG sites that were hyper-methylated in the HIV-infected group and 38 CpG sites that were hypo-methylated in the HIV-infected group. Six hyper-methylated CpG sites were in EBF4, which codes for a transcription factor involved in B-cell maturation. The top hypomethylated site was in the promoter region of NLRC5, encoding a transcription factor that regulates major histocompatibility complex (MHC) class I molecule expression. Using a differentially-methylated region (DMR) approach, we found 315 DMRs between groups, including 28 regions encompassing 686 CpG sites on chromosome 6. A large number of the genes identified in both the CpG site and DMR approaches were located in the MHC region on chromosome 6, which plays an important role in the adaptive immune system. This study provides the first evidence that changes in the epigenome are detectable in children with perinatally-acquired HIV infection on suppressive ART started at an early age.

Highlights

Despite the success of programs to prevent mother-to-child HIV transmission (MTCT) and improve accessibility of antiretroviral therapy (ART), an estimated 2.6 million children live with HIV globally, 90% of them in sub-Saharan Africa[1]
Another study of 261 HIV-infected and 117 HIV-uninfected adults identified 20 CpG sites associated with HIV infection, including 2 CpG sites in NLRC5, which codes for a key regulator of major histocompatibility complex (MHC) class I gene expression[16]
ART was started at a mean (SD) age of 7.7 (6.1) months; by design 60 started ART

Summary

Introduction

Despite the success of programs to prevent mother-to-child HIV transmission (MTCT) and improve accessibility of antiretroviral therapy (ART), an estimated 2.6 million children live with HIV globally, 90% of them in sub-Saharan Africa[1]. In the absence of a cure for HIV, this cohort will live with the burden of the disease and remain on lifelong ART as they grow into adolescence and adulthood It is well-established that perinatally-acquired HIV has persistent effects on long-term health outcomes, even after early treatment. A study of 137 HIV-infected, ART-treated white non-Hispanic males (mean age 48 years) and 44 uninfected males identified 81,361 CpG sites associated with HIV infection, including decreased DNAm in the chromosomal region encoding the human leukocyte antigen (HLA) locus[15]. Another study of 261 HIV-infected (mean age 49 years, 96.9% male, 67% African-American, 79% on ART) and 117 HIV-uninfected adults identified 20 CpG sites associated with HIV infection, including 2 CpG sites in NLRC5, which codes for a key regulator of major histocompatibility complex (MHC) class I gene expression[16]. As many of the behavioral risk factors that may lead to epigenetic changes (e.g. smoking, physical inactivity, and drug use) are not predominant in early childhood, it is important to study epigenetic processes in adults, and in children

Methods

Results

Conclusion