Accelerated epigenetic aging persists in adolescents with perinatally acquired HIV
Presenter: Sarah Heany, PhD, University of Cape Town, Psychiatry and Mental Health, Cape Town, South Africa
Persistent accelerated epigenetic aging is associated with altered neuroimaging and immune biomarkers in a longitudinal cohort of vertically acquired HIV-positive adolescents. Presented July 24, 2023.
Epigenetic aging as detected in DNA methylation patterns is accelerated and persists longitudinally in adolescents with perinatally acquired HIV.
Three-year follow-up of the Cape Town Adolescent Antiretroviral Cohort (CTAAC) study showed that multiple measures of epigenetic aging remain increased in HIV-positive adolescents across a 3-year period, and associations between epigenetic aging, viral biomarkers, and alterations in brain micro- and macrostructure also persist, said lead investigator Sarah Heany, PhD, University of Cape Town, Psychiatry and Mental Health, Cape Town, South Africa.
Little is known about the development of chronic diseases in perinatally acquired HIV-positive children. These authors previously showed that aging was accelerated in children living with perinatally acquired HIV, based on discrepancies between epigenetic and chronological age.1 Their study used an algorithm, developed by co-author Steve Horvath, PhD, ScD, University of California, Los Angeles, based on the methylation patterns of 353 cytosine-phosphate-guanine (CpG) points in the genome, which is referred to as the “epigenetic clock.” The methylation “is a chemical modification to the DNA that controls gene expression and can silence certain genes. It’s kind of an ‘epigenetic rust’ that accumulates on the DNA during life,” said Dr. Heany.
The data presented are 3-year follow-up longitudinal patterns of epigenetic aging and their association with cognition and whole-brain structural changes in HIV-positive participants and controls in the CTAAC study. A total of 96 participants (60 HIV-positive individuals and 36 HIV-uninfected controls) in the sample underwent brain imaging. Their average age was 10.8 years at baseline and 13.8 years at follow-up. The controls were well matched in terms of age, sex, and sociodemographics. The average age at the time of antiretroviral therapy initiation was 3 years. About one-third (32%) of the HIV-positive group had viral load values higher than 40 copies/mL, and their average CD4 T-cell count was 747.5 cells/mm3.
The Illumina EPIC array was used to generate blood DNA methylation data at baseline and follow-up. At both time points, the epigenetic clock software estimated two measures of epigenetic age acceleration: extrinsic epigenetic accelerated aging (EEAA) and age acceleration difference (AAD). Each participant completed neurocognitive testing and structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI).
“We found more variance in aging patterns in aging patterns in the HIV-positive group versus controls,” said Dr. Heany. “We think this is due to a different immune response to various treatment protocols.” At baseline, the HIV-positive cohort had a mean DNA methylation age (epigenetic age) that was 2.3 years older compared with the controls, and at follow-up, the mean DNA methylation age was 2.4 years greater in the HIV-infected participants, even though chronological ages were well matched, demonstrating an increased persistence of epigenetic aging longitudinally. The mean EEAA was 1.68 in the HIV-positive adolescents and –2.80 in the controls, indicating accelerated aging in the HIV-infected cohort (a positive value indicates that the epigenetic age is higher than expected, based on chronological age). The mean AAD was also higher at baseline and follow-up in the participants with perinatally acquired HIV versus controls.
Measures of cognitive functioning (ie, executive function, spatial acuity) were not associated with epigenetic aging.
Epigenetic aging was positively associated with whole-brain gray matter volume and alterations in white matter structure. “For the white matter, the aging was associated with less fractional anisotropy or directionality of the white matter tracts, and was also associated with increased diffusion of the white matter, which is something that lessens the white matter’s structural integrity,” she said. “It is thought that the gray matter alterations may be due to disruptions in efficient gray matter pruning in this young cohort, and the white matter results are something that is often seen in cases of systemic inflammation.” The differences between the HIV-positive group and the controls were similar over time on both MRI and DTI.
The viral load was inversely related to epigenetic aging, highlighting the importance of disease management during the developmental stage, she said.
Reference
- Horvath S, Stein DJ, Phillips N, et al. Perinatally acquired HIV infection accelerates epigenetic aging in South African adolescents. AIDS 2018; 32(11):1465–1474. doi:10.1097/QAD.0000000000001854
The authors report no conflicts of interest.
The research was supported by the National Institute of Child Health and Human Development.