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.
Highlights
40 million people worldwide are infected with the Human Immunodeficiency Virus (HIV)
HIV involvement of the central nervous system (CNS) continues to be a significant problem despite successful use of combination antiretroviral therapy, which has decreased the incidence of HIV-associated dementia (HAD) but has not greatly affected the prevalence of milder forms of HIVassociated neurocognitive disorders (HAND) [3]
The relatively high rate of cognitive impairment in the non-METH cases may reflect brain injury that occurred before combination antiretroviral therapy (cART) became available to these subjects, whose exposure to ARV on average was significantly shorter than the METH group
Summary
40 million people worldwide are infected with the Human Immunodeficiency Virus (HIV). HIV involvement of the CNS continues to be a significant problem despite successful use of combination antiretroviral therapy (cART), which has decreased the incidence of HAD but has not greatly affected the prevalence of milder forms of HIVassociated neurocognitive disorders (HAND) [3]. This is probably due to several conditions, including drug resistance, cART toxicity and comorbidity factors such as aging, use of drugs of dependence and Hepatitis C virus infection [4,5]. As a result of the association of METH use with high-risk sexual behavior, increased HIV transmission, and the development of antiretroviral drug resistance, METH plays an important role in driving the course of the HIV epidemic in the United States [9]
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