High frequency of mitochondrial DNA mutations in HIV‐infected treatment‐experienced individuals

Abstract

ObjectivesWe recently observed a decrease in deoxyribonucleotide (dNTP) pools in HIV‐infected individuals on antiretroviral therapy (ART). Alterations in dNTPs result in mutations in mitochondrial DNA (mtDNA) in cell culture and animal models. Therefore, we investigated whether ART is associated with mitochondrial genome sequence variation in peripheral blood mononuclear cells (PBMCs) of HIV‐infected treatment‐experienced individuals.MethodsIn this substudy of a case−control study, 71 participants were included: 22 ‘cases’, who were HIV‐infected treatment‐experienced patients with mitochondrial toxicity, 25 HIV‐infected treatment‐experienced patients without mitochondrial toxicity, and 24 HIV‐uninfected controls. Total DNA was extracted from PBMCs and purified polymerase chain reaction (PCR) products were subjected to third‐generation sequencing using the PacBio Single Molecule Real‐Time (SMRT) sequencing technology. The sequences were aligned against the revised Cambridge reference sequence for human mitochondrial DNA (NC_012920.1) for detection of variants.ResultsWe identified a total of 123 novel variants, 39 of them in the coding region. HIV‐infected treatment‐experienced patients with and without toxicity had significantly higher average numbers of mitochondrial variants per participant than HIV‐uninfected controls. We observed a higher burden of mtDNA large‐scale deletions in HIV‐infected treatment‐experienced patients with toxicity compared with HIV‐uninfected controls (P = 0.02). The frequency of mtDNA molecules containing a common deletion (mt.δ4977) was higher in HIV‐infected treatment‐experienced patients with toxicity compared with HIV‐uninfected controls (P = 0.06). There was no statistically significant difference in mtDNA variants between HIV‐infected treatment‐experienced patients with and without toxicity.ConclusionsThe frequency of mtDNA variants (mutations and large‐scale deletions) was higher in HIV‐infected treatment‐experienced patients with or without ART‐induced toxicity than in uninfected controls.

Mitochondrial DNA somatic mutation burden and heteroplasmy are associated with chronological age, smoking, and HIV infection

“…Furthermore, we validated our results using data from an independent cohort enrolled at Yale New Haven Hospital, New Haven, Connecticut, USA (Li et al, ) (Li et al, ). We included in the current analysis data from study participants living with HIV who were either current smokers or never smokers.…”

“…The second study demonstrated increased mtDNA deletions in muscle tissue from participants treated with HIV therapy ( n = 21) compared to those who were therapy‐naïve ( n = 11), but showed no evidence of increased mtDNA heteroplasmy (Payne et al, ). Finally Li et al () reported a significantly higher frequency of mtDNA variants among persons living with HIV and treated with cART ( n = 47) compared to HIV‐negative controls ( n = 24).…”

“…To date, two small studies (Martin et al, ; Payne et al, ) and one larger study (Li et al, ) have investigated mtDNA heteroplasmic point mutations in persons living with HIV. The first one suggested that HIV therapy‐experienced participants showed a higher frequency of blood mtDNA heteroplasmy ( n = 5/16) than HIV therapy‐naïve participants ( n = 0/10).…”

“…Previous studies on mtDNA mutation burden in HIV have had limited sample size and focused on HIV and/or HIV therapy (Martin et al, ; Payne et al, ) without considering other potential confounders. Larger studies have either concentrated on heteroplasmic mtDNA mutations (Li et al, ) or used assays not sensitive enough to detect low‐frequency somatic mutations (Jitratkosol et al, ).…”

Antiretroviral Therapy for Mitochondrial Toxicity in HIV-Infected Pregnant Women

“…In fact, mitochondrial defections have been associated with increased rates of preterm delivery, stillbirth, IUGR, and sudden infant death [5][6][7][8]. Reviewing the literature, ART can induce subclinical transplacental mitochondrial lesions.…”