title: 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.
authors: Department of Neuroscience, University of California San Diego, La Jolla, California, United States of America.
authors: Paula
authors: P
authors: Desplats
authors: Department of Pathology, University of California San Diego, La Jolla, California, United States of America.
authors: Wilmar
authors: W
authors: Dumaop
authors: Department of Neuroscience, University of California San Diego, La Jolla, California, United States of America.
authors: Peter
authors: P
authors: Cronin
authors: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors: Sara
authors: S
authors: Gianella
authors: Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
authors: Steven
authors: S
authors: Woods
authors: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors: Scott
authors: S
authors: Letendre
authors: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors: David
authors: D
authors: Smith
authors: Department of Neuroscience, University of California San Diego, La Jolla, California, United States of America; Department of Pathology, University of California San Diego, La Jolla, California, United States of America.
authors: Eliezer
authors: E
authors: Masliah
authors: Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
authors: Igor
authors: I
authors: Grant
mesh_terms: D000328:Adult; D019969:Amphetamine-Related Disorders / Q000235:genetics* / Q000503:physiopathology; D001344:Autopsy; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000821:virology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D053263:Gene Regulatory Networks; D015658:HIV Infections / Q000235:genetics* / Q000503:physiopathology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human