Mitochondrial injury and cognitive function in HIV infection and methamphetamine use

Abstract

Objective In this work we evaluated the association of human immunodeficiency virus (HIV) infection and methamphetamine (METH) use with mitochondrial injury in the brain and its implication on neurocognitive impairment. Design Mitochondria carry their genome (mtDNA) and play a critical role in cellular processes in the central nervous system. METH is commonly used in HIV-infected populations. HIV infection and METH use can cause damage to mtDNA and lead to neurocognitive morbidity. We evaluated HIV infection and METH use with mitochondrial injury in the brain. Methods We obtained white and gray matter from Brodmann’s areas (BA) BA7, BA8, BA9, and BA46 of a) HIV-infected individuals with history of past METH use (HIV+METH+, n=16), b) HIV-infected individuals with no history of past METH use (HIV+METH−, n=11), and c) HIV-negative controls (HIV−METH−, n=30). We used the “common deletion,” a 4,977 bp mutation, as a measurement of mitochondrial injury, and quantified levels of mtDNA and “common deletion” by droplet digital PCR, and evaluated in relation to neurocognitive functioning (Global Deficit Score [GDS]). Results Levels of mtDNA and mitochondrial injury were highest in white matter of BA46. A higher relative proportion of mtDNA carrying the “common deletion” was associated with lower GDS (p<0.01) in HIV+METH+ but higher GDS (p<0.01) in HIV+METH−. Conclusions Increased mitochondrial injury was associated with worse neurocognitive function in HIV+METH− individuals. Among HIV+METH+ individuals, an opposite effect was seen.

HIV in the cART era and the mitochondrial: immune interface in the CNS

“…Neuropathological studies showed accumulation of mtDNA damage in the frontal cortex of HAND patients (Zhang et al, 2012), which has implications for the processes of mitochondrial biogenesis and ATP production. A recent study found similar markers of mitochondrial damage in a cohort of HIV+ brains that were stratified by use of methamphetamine (Var et al, 2016). In this study, increased mitochondrial injury in Brodmann area 46 of frontal cortices was associated with worse neurocognitive function in HIV+METH À individuals (Var et al, 2016).…”

Increased cell-free mitochondrial DNA is a marker of ongoing inflammation and better neurocognitive function in virologically suppressed HIV-infected individuals

“…DNA was extracted from CSF supernatant samples using QIAamp DNA Mini Kit (Qiagen, Hilden, Germany) per manufacturer’s protocol. Levels of mtDNA were measured by droplet digital PCR (ddPCR, Bio-Rad, Hercules, CA) using primer-probes combinations targeting the mitochondrial NADH dehydrogenase 2 gene (MT-ND2, Integrated DNA Technologies, IA) and the human genomic DNA (gDNA) by targeting the Ribonuclease P protein subunit p30 gene (RPP30, Integrated DNA Technologies, IA), using ZEN quenched probes [14]. Each sample was run in triplicate in a 20μL of reaction, which consisted of 10μL of 2× Bio-Rad supermix for probes, 1μL of either 20× Primer/FAM-Zen ND2 mix or 20× Primer/HEX-Zen RPP30 mix, 4μL of molecular grade water, and 5μL of total DNA, using the following conditions: (1) an initial activation of 95°C for 10 minutes, (2) 55 cycles of 94°C for 30 seconds and 60°C for 1 min, (3) enzyme inactivation at 98°C for 10 minutes, and 4°C hold.…”

Effects of HIV and Methamphetamine on Brain and Behavior: Evidence from Human Studies and Animal Models

“…Recent studies using postmortem HIV-infected brains have addressed nuclear DNA methylation, mitochondrial DNA injury, and cerebral gliosis (Desplats et al 2014; Soontornniyomkij et al 2016; Var et al 2016). Epigenetic changes were investigated in the frontal cortex of HIV-infected individuals with or without Meth dependence (Desplats et al 2014).…”