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Perinatally acquired HIV infection accelerates
epigenetic aging in South African adolescents
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"This is the first study to show that a) perinatally acquired HIV infection is associated with
epigenetic age acceleration in blood, and b) extrinsic epigenetic age acceleration is associated
with lower cognitive functioning in these adolescents......To our knowledge, this is the first cohort study to examine the impact of epigenetic age acceleration in adolescents living with HIV and the association with cognitive function. The study took place in South Africa, one of the countries most affected by HIV/AIDS with the highest rate of new HIV infections in the world. Despite a mean age of initiation of ART treatment of 3.4 years and usage for more than 7 years, considerable cognitive impairment is apparent. Longitudinal follow-up of our cohort will be crucial for determining the impact of epigenetic aging in adolescents living with HIV. Correlates of epigenetic aging need to be elucidated, including associations with measures of viral load, treatment duration, concurrent infections, and ART prescription and treatment adherence, in order to understand their impact on the long-term development of neurocognitive disorders in pediatric HIV."
"Despite high correlations, epigenetic age estimates can deviate substantially from chronological age at the individual level. After adjusting DNAm age for chronological age, one arrives at measures of epigenetic age acceleration. Here we focus on two widely used measures of
epigenetic age acceleration denoted by AgeAccelerationResidualand EEAA, respectively. By definition, both measures are independent of chronological age (at the time of blood draw). For both measures of age acceleration, positive (negative) values indicate that the blood sample is older (younger) than expected based on chronological age. The mathematical definition of these measures is briefly reviewed here. AgeAccelerationResidual is defined as the (raw) residual resulting from regressing the multi-tissue DNAm age estimate on chronological age. By definition, AgeAccelerationResidual is independent of chronological age. Extrinsic epigenetic age acceleration (EEAA) can be interpreted as an enhanced version of the Hannum measure of DNAm age estimator because it up-weights the contributions of age-related blood cell counts [32, 46].
In a recent large scale meta-analysis involving over 13 thousand subjects from 13 cohorts, we have shown that both AgeAccelerationResidual and EEAA are predictive of mortality, independent of chronological age, even after adjusting for additional risk factors, and within the racial/ethnic groups that we examined (Caucasians, Hispanics, African Americans) [32]. The EEAA measure is attractive because a) it exhibited the strongest predictive association with all-cause mortality [32] and b) it revealed the strongest association with cognitive functioning measures in our study. AgeAccelerationResidual is attractive because a) it is less confounded by changes in blood cell composition, b) it applies to all tissue samples, and c) it is particularly accurate in adolescents, and d) we previously used it in our study of HIV+ adults [10, 15]."
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AIDS May 8 2018 - Horvath, Stevea,b; Phillips, Nicolec; Heany, Sarah, J.c; Kobor, Michael, S.d; Lin, David, TSd; Myer, Landone,f; Zar, Heather, J.g; Stein, Dan, J.c; Levine, Andrew, J.h; Hoare, Jacquelinec
"HIV+ adolescents exhibit increased levels of AgeAccelerationResidual and EEAA compared to HIV- controls (Figure 1A,B). Increased epigenetic age acceleration can even be observed in HIV+ individuals whose viral load is not
detectable (VL < 50 copies/mL).....We correlated both measures of epigenetic age acceleration with cognitive functioning measures but found significant correlations only for the extrinsic measure of epigenetic age acceleration: EEAA is significantly associated with overall cognitive impairment status.....These findings suggest that an epigenetically older immune system is associated with lower cognitive functioning....A multivariate linear model analysis reveals that
both HIV infection and EEAA are independently associated with cognitive performance measures: executive functioning, working memory, and processing speed (Model 1 in Table 3).....Multivariate regression model analysis revealed that EEAA remained negatively associated with executive functioning (p=0.023), working memory (p=0.049) and processing speed (p=0.024) even after adjusting for HIV status, educational level (assessed by highest grade, and repeated grade), ethnicity, and household income.........we recently found evidence that HIV infection is associated with accelerated epigenetic aging based on the epigenetic clock[15] in both brain and peripheral blood mononuclear cells [10]. That is, brains of adults infected with HIV demonstrated age acceleration of 7.4 years compared to uninfected controls, and 5.2 years in peripheral blood mononuclear cells, findings that have been validated by other groups[12-14]. Furthermore, we have found that accelerated epigenetic aging can be observed in brain tissue samples of adults diagnosed pre-mortem with HIV-associated neurocognitive disorders (HAND) [16]. As such, the epigenetic clock method lends itself for detecting accelerated biological aging effects due to HIV infection in adult cohorts, and for determining whether accelerated epigenetic aging has significant health consequences. However, it is not yet known whether accelerated epigenetic aging effects are already detectable in adolescents and, if so, whether these epigenetic changes correlate with measures of cognitive performance, immune status and ART treatment regimen"
Objective: Recent studies demonstrate that infection with the Human Immunodeficiency Virus-1 (HIV) is associated with accelerated aging effects in adults according to a highly accurate epigenetic biomarker of aging known as epigenetic clock. However, it not yet known whether epigenetic age acceleration occurs as early as adolescence in perinatally HIV-infected (PHIV+) youth.
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Design: Observational study of PHIV and HIV-uninfected adolescents enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC) Study.
Methods: The Illumina EPIC array was used to generate blood DNA methylation data from 204 PHIV and 44 age-matched, uninfected (HIV-) adolescents aged 9 to 12 years old. The epigenetic clock software and method was used to estimate two measures of epigenetic age acceleration. Each participant completed a comprehensive neuropsychological test battery upon enrolment to CTAAC.
Results: HIV is associated with biologically older blood in PHIV+ adolescents according to both measures of epigenetic age acceleration. One of the measures, extrinsic epigenetic age acceleration, is negatively correlated with measures of cognitive functioning (executive functioning, working memory, processing speed).
Conclusions: Overall, our results indicate that epigenetic age acceleration in blood can be observed in PHIV+ adolescents and that these epigenetic changes accompany poorer cognitive functioning.
INTRODUCTION
Childhood HIV infection and its consequences on development remain a significant public health issue in several countries. There are an estimated 2.3 million children under the age of 15 years living with HIV/AIDS in sub-Sahara Africa, with 330,000 in South Africa (SA) alone. A growing number of perinatally HIV-infected (PHIV+) children in SA are surviving into adolescence, due to earlier diagnosis and initiation of effective antiretroviral therapies (ARTs).
However, as elsewhere, PHIV+ adolescents face unique health issues, particularly related to neurocognitive and neurobiological complications resulting from HIV that will adversely hinder their transition into adult roles. HIV infection leads to changes in the structure and function of the central nervous system, which has significant consequences on academic performance and psychosocial functioning that compound over the lifespan[1-4]. Recent data from our lab indicates a pattern of damaged neuronal microstructure, smaller gray matter volumes, reduced cortical surface area and decreased gyrification in SA adolescents living with HIV and suggests abnormal neurodevelopment in perinatally infected adolescents[5]. The South African Department of Health first line antiretroviral (ART) regimen for children older than 3 years and more than 10kg is Abacavir (ABC) + lamivudine (3TC) + efavirenz (EFV). First-line treatment failure may be a key factor associated with CNS damage in perinatally infected adolescents.
Our analysis of ART line (first/second/third) (variable ARV.line) reveals that adolescents who are on second or third line ART treatment are more likely to have accelerated ageing (Figure 1C,D). Both AgeAccelerationResidual and EEAA remain significantly associated with current CD4 T cell counts and ARV.line even after adjusting for viral load, educational status, ethnicity, and other potential confounders (Table 2). Epigenetic age acceleration exhibits substantial heterogeneity in HIV+ adolescents. In HIV+ adolescents, age at ART initiation nor ART duration were significantly correlated with measures of epigenetic age acceleration nor with cognitive assessments. Similarly, household income was not correlated with epigenetic age acceleration in HIV+ adolescents. However, CD4+ T cell counts was negatively correlated with epigenetic age acceleration in HIV+ adolescents (Figure 1). A multivariate model analysis reveals that HIV viral load, current CD4 T cell count, ethnicity, ARV duration, ARV.line, and education explain only 8.8 percent of the variable in AgeAcceleration but 17.3 percent of the variation of EEAA in HIV+ adolescents (Table 2).
Extrinsic epigenetic age acceleration relates to cognitive functioning measures
We correlated both measures of epigenetic age acceleration with cognitive functioning measures but found significant correlations only for the extrinsic measure of epigenetic age acceleration: EEAA is significantly associated with overall cognitive impairment status (Figure 2A), and more specifically with the following cognitive domains: attention, working memory, executive functioning, and processing speed (Figure 2B-E). This association does not reflect confounding by HIV status since we continue to observe significant associations between EEAA and working memory, executive functioning, and processing speed (Figure 2F-I) after restricting the analysis to HIV+ individuals. These findings suggest that an epigenetically older immune system is associated with lower cognitive functioning. A multivariate linear model analysis reveals that both HIV infection and EEAA are independently associated with cognitive performance measures: executive functioning, working memory, and processing speed (Model 1 in Table 3).
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