Epigenetic Alterations in the Brain Associated with HIV-1 Infection and Methamphetamine Dependence

Abstract

HIV involvement of the CNS continues to be a significant problem despite successful use of combination antiretroviral therapy (cART). Drugs of abuse can act in concert with HIV proteins to damage glia and neurons, worsening the neurotoxicity caused by HIV alone. Methamphetamine (METH) is a highly addictive psychostimulant drug, abuse of which has reached epidemic proportions and is associated with high-risk sexual behavior, increased HIV transmission, and development of drug resistance. HIV infection and METH dependence can have synergistic pathological effects, with preferential involvement of frontostriatal circuits. At the molecular level, epigenetic alterations have been reported for both HIV-1 infection and drug abuse, but the neuropathological pathways triggered by their combined effects are less known. We investigated epigenetic changes in the brain associated with HIV and METH. We analyzed postmortem frontal cortex tissue from 27 HIV seropositive individuals, 13 of which had a history of METH dependence, in comparison to 14 cases who never used METH. We detected changes in the expression of DNMT1, at mRNA and protein levels, that resulted in the increase of global DNA methylation. Genome-wide profiling of DNA methylation in a subset of cases, showed differential methylation on genes related to neurodegeneration; dopamine metabolism and transport; and oxidative phosphorylation. We provide evidence for the synergy of HIV and METH dependence on the patterns of DNA methylation on the host brain, which results in a distinctive landscape for the comorbid condition. Importantly, we identified new epigenetic targets that might aid in understanding the aggravated neurodegenerative, cognitive, motor and behavioral symptoms observed in persons living with HIV and addictions.

DNA Methylation, Substance Use and Addiction: a Systematic Review of Recent Animal and Human Research from a Developmental Perspective

“…One global methylation study found decreased DNAm in the blood of alcohol drinkers (Alu, not LINE-1 [39]). Results contrast those of increased global methylation identified in the frontal cortex of HIV+ methamphetamine users versus non users [40], as well as in the blood of methadone-substituted former opiate addicts, an effect which was also replicated in independent sample of opioid-treated patients [41]. Candidate gene studies focused mainly on genes involved in neural function, most likely guided by existing neurochemical data regarding addiction on animals and humans.…”

“…Hypomethylation was also observed in long terminal repeat (LTR) regions of retrotransposons in the superior frontal cortex of postmortem alcohol users [56]. Other important pathways related to apoptosis [52,54,55], metabolism [53], as well as GABA and dopamine systems [40,53].…”

Can research at the end of life be a useful tool to advance HIV cure?

“…Most of our understanding of deep HIV reservoirs has come from autopsy studies, but these previous studies had variable ART intake and limited ante-mortem characterization that can be compared to post-mortem measures [12, 30, 31]. Also, there is typically a significant delay in time from ante-mortem visits until death (for example the average time between the last clinical assessment and death is 262.6 days (Standard deviation: 402.7 days) and is rarely < 6 months in the California NeuroAIDS Tissue Network [32]).…”

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).…”

“…Epigenetic changes were investigated in the frontal cortex of HIV-infected individuals with or without Meth dependence (Desplats et al 2014). Meth was associated with increased expression levels of DNMT1 gene (DNA (cytosine-5)-methyltransferase-1 enzyme involved in the maintenance of DNA methylation) and increased levels of global DNA methylation that correlated directly with HIV-1 RNA levels.…”