Mitochondrial Impairment in Well-Suppressed Children with Perinatal HIV-Infection on Antiretroviral Therapy

Abstract

Mitochondrial impairment is reported in HIV-infected children receiving antiretroviral therapy (ART), as well as those naive to ART. Whether mitochondrial function recovers with early initiation of ART and sustained viral suppression on long-term ART is unclear. In this study, we evaluate mitochondrial markers in wellsuppressed perinatally HIV-infected children initiated on ART early in life. We selected a cross-sectional sample of 120 HIV-infected children with viral load <400 copies/mL and 60 age-matched uninfected children (22 HIV-exposed uninfected) enrolled in a cohort study in Johannesburg, South Africa. Complex IV (CIV) and citrate synthase (CS) activity were measured by spectrophotometry. Mitochondrial DNA (mtDNA) content relative to nuclear DNA (nDNA) was measured by quantitative real-time polymerase chain reaction and expressed as copies/nDNA. Mitochondrial markers were impaired in HIV-infected children, including lower mean CIV activities [1.76 vs. 1.40 optical densities (OD)/min], higher risk of a CIV/CS ratio £0.22 (third quartile; odds ratio = 3.03, 95% confidence interval: 1.38-6.66), and lower mtDNA content. Children with shorter versus longer ART duration (<6.3 vs. ‡6.3 years) had lower means of CIV activity (1.22-1.58 OD/min) and mtDNA content (386-907 copies/nDNA). There were no differences in mitochondrial markers between children who started ART earlier (<6 months) or later (6-24 months). CIV activity was impaired in children with lower height-for-age Z-scores (HAZs). Despite early treatment and prolonged viral suppression, HIVinfected children had detectable mitochondrial impairment, particularly among those with stunted growth. Further study is required to determine if continued treatment will lead to full recovery of mitochondrial function in HIV-infected children.

HIV and cardiovascular disease: the role of inflammation

“…Mitochondrial function and substrate utilization are perturbed in young children with PHIV [96,97]. Despite early ART treatment and viral suppression, cross-sectional analyses suggest that young PHIV children (mean age ¼ 6 years) have mitochondrial impairment as measured by complex IV, citrate synthase and mitochondrial DNA content [97]. It is unclear, however, whether decades of ART will allow for recovery or further declines in mitochondrial function.…”

Contemporary Antiretroviral Therapy Dysregulates Iron Transport and Augments Mitochondrial Dysfunction in HIV-Infected Human Microglia and Neural-Lineage Cells

“…Long-acting ARV formulations [e.g., non-nucleoside reverse-transcriptase inhibitors, INSTIs, and TFV] have been tested in clinical trials, and the metabolic toxicities of these formulations are a concern [68]. Cumulative effects of cART may be particularly impactful in utero or in children and young adults with HIV, who currently require lifelong treatment and whose brain development is ongoing when therapy is initiated [69][70][71][72]. Our results also raise the possibility that chronic cellular iron accumulation due to HIV, and augmented by cART, contribute to cellular senescence and accentuated aging phenotypes in PWH [73,74], including increased brain aging and HAND.…”

Health Outcomes at School Age among Children Who Are HIV-Exposed but Uninfected with Detected Mitochondrial DNA Depletion at One Year

“…Another study, although not showing an association, identified CHEU with possible mitochondrial dysfunction based on neurologic manifestations including febrile or afebrile seizures and delay in cognitive development [ 28 ]. To our knowledge, only one study reported lower height-for-age Z-scores among HIV-infected children with lower mtDNA content and decreased complex IV enzymatic activity from the mitochondrial respiratory chain [ 29 ]. Children herein who accumulated ARV exposure during pregnancy and during the first year of life, had few health problems, growth impairment, or hematological abnormalities at six years of age.…”