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

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.

SUBMITTER: Shiau S

PROVIDER: S-EPMC6642153 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Shiau Stephanie S Strehlau Renate R Wang Shuang S Violari Avy A Do Catherine C Patel Faeezah F Liberty Afaaf A Krupska Izabela I Arpadi Stephen M SM Foca Marc M Coovadia Ashraf A Abrams Elaine J EJ Tycko Benjamin B Terry Mary Beth MB Kuhn Louise L

Scientific reports 20190719 1

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 fou ...[more]

PMID: 31324826

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Project description:IntroductionThere are limited data on Tuberculosis (TB) in adolescents with perinatally acquired HIV (APHIV). We examined the incidence and determinants of TB infection and disease in the Cape Town Adolescent Antiretroviral Cohort (CTAAC).MethodsYouth between nine and fourteen years on antiretroviral therapy (ART) for more than six months in public sector care, and age-matched HIV-negative adolescents, were enrolled between July 2013 through March 2015 and followed six-monthly. Data were censored on 31 October 2018. Symptom screening, chest radiograph, viral load, CD4 count, QuantiFERON (QFT) and sputum for Xpert MTB/RIF, microscopy, culture and sensitivity were performed annually. TB infection was defined by a QFT of >0.35 IU/mL. TB diagnosis was defined as confirmed (culture or Xpert MTB/RIF positive) or unconfirmed (clinical diagnosis and started on TB treatment). Analyses examined the incidence and determinants of TB infection and disease.ResultsOverall 496 HIV+ and 103 HIV-negative participants (median age at enrolment 12 years (interquartile range, IQR 10.6 to 13.3) were followed for a median of 3.1 years (IQR 3.0 to 3.4); 50% (298/599) were male. APHIV initiated ART at median age 4.4 years (IQR 2.1 to 7.6). At enrolment, 376/496 (76%) had HIV viral load <40 copies/mL, median CD4 count was 713 cells/mm3 and 179/559 (32%) were QFT+, with no difference by HIV status (APHIV 154/468, 33%; HIV negative 25/91, 27%; p = 0.31). The cumulative QFT+ prevalence was similar (APHIV 225/492, 46%; 95%CI 41% to 50%; HIV negative 44/98, 45%; 95% CI 35% to 55%; p = 0.88). APHIV had a higher incidence of all TB disease than HIV-negative adolescents (2.2/100PY, 95% CI 1.6 to 3.1 vs. 0.3/100PY, 95% CI 0.04 to 2.2; IRR 7.36, 95% CI 1.01 to 53.55). The rate of bacteriologically confirmed TB in APHIV was 1.3/100 PY compared to 0.3/100PY for HIV-negative adolescents, suggesting a fourfold increased risk of developing TB disease in APHIV despite access to ART. In addition, a positive QFT at enrolment was not predictive of TB in this population.ConclusionsHigh incidence rates of TB disease occur in APHIV despite similar QFT conversion rates to HIV-negative adolescents. Strategies to prevent TB in this vulnerable group must be strengthened.

Project description:BackgroundAcross numerous settings, bone mineral density for age and sex is lower in children/adolescents living with perinatally-acquired HIV (PHIV) compared to uninfected peers. We assessed incidences of any fracture/any long bone fracture, and osteoporosis prevalence in PHIV and HIV-exposed uninfected (PHEU) participants in the Pediatric HIV/AIDS Cohort Study (PHACS).MethodologyLifetime history of fracture events from birth up to age 20 years was obtained by chart review and/or interview, including age at fracture, mechanism, and bone(s) fractured. Poisson regression models were fit comparing fracture incidence by HIV status adjusted for age, sex, and race, with effect modification by age (<6, ≥6 yr).ResultsPHIV (N = 412) were older (median 17.5 vs 16.7 yr) and more frequently reported black race (72% vs 61%) than PHEU children/adolescents (N = 206). 17% of PHIV and 12% of PHEU ever reported a fracture. Among children <6 yr, the adjusted incidence rate ratio of ≥1 fracture was higher (7.23; 95% CI 0.98, 53.51) in PHIV than PHEU, but similar among children/adolescents ≥6 years (1.20; 95% CI: 0.77, 1.87). Results were similar for long bone fracture. The most common fracture mechanisms were falling to the ground from a standing height (23.6% PHIV vs 8.8% PHEU) and sports injuries (21.3% vs 32.4%), and the most commonly fractured sites were the forearm and small bones of the wrist/hands. None of the children had osteoporosis.ConclusionsAmong children/adolescents ≥6 yr of age, fractures were similar by perinatal HIV status. Prospective, targeted collection of fracture history will be necessary to determine rates of fracture as PHIV and PHEU age into adulthood.SummaryLifetime fracture history was collected in children/adolescents living with perinatally-acquired HIV (PHIV) and HIV-exposed uninfected (PHEU) children from birth up to age 20 years. Fracture incidence was higher in PHIV compared to PHEU among children <6 years old, but not among older children/adolescents.

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

Publications

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

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