HIV-1, methamphetamine and astrocytes at neuroinflammatory Crossroads

Abstract

As a popular psychostimulant, methamphetamine (METH) use leads to long-lasting, strong euphoric effects. While METH abuse is common in the general population, between 10 and 15% of human immunodeficiency virus-1 (HIV-1) patients report having abused METH. METH exacerbates the severity and onset of HIV-1-associated neurocognitive disorders (HAND) through direct and indirect mechanisms. Repetitive METH use impedes adherence to antiretroviral drug regimens, increasing the likelihood of HIV-1 disease progression toward AIDS. METH exposure also directly affects both innate and adaptive immunity, altering lymphocyte numbers and activity, cytokine signaling, phagocytic function and infiltration through the blood brain barrier. Further, METH triggers the dopamine reward pathway and leads to impaired neuronal activity and direct toxicity. Concurrently, METH and HIV-1 alter the neuroimmune balance and induce neuroinflammation, which modulates a wide range of brain functions including neuronal signaling and activity, glial activation, viral infection, oxidative stress, and excitotoxicity. Pathologically, reactive gliosis is a hallmark of both HIV-1- and METH-associated neuroinflammation. Significant commonality exists in the neurotoxic mechanisms for both METH and HAND; however, the pathways dysregulated in astroglia during METH exposure are less clear. Thus, this review highlights alterations in astrocyte intracellular signaling pathways, gene expression and function during METH and HIV-1 comorbidity, with special emphasis on HAND-associated neuroinflammation. Importantly, this review carefully evaluates interventions targeting astrocytes in HAND and METH as potential novel therapeutic approaches. This comprehensive overview indicates, without a doubt, that during HIV-1 infection and METH abuse, a complex dialog between all neural cells is orchestrated through astrocyte regulated neuroinflammation.

Methamphetamine addiction: involvement of CREB and neuroinflammatory signaling pathways

“…2F, 2G, 3D, 3E, also see Krasnova et al 2010). Reactive astrocytes can secrete cytokines and chemokines (Ramesh et al 2013) that participate in METH-induced neuroinflammatory responses (Borgmann and Ghorpade, 2015). The data showing evidence of METH-induced inflammatory response in the brain are summarized in Table 4.…”

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

“…The toxic effects of either Meth or Tat or both on the blood-brain barrier, neurons, and glial cells have been investigated extensively in in vitro cell systems (Cisneros and Ghorpade 2012; Borgmann and Ghorpade 2015; Mediouni et al 2015). Both Meth and Tat inhibited astroglial Wnt/β-catenin signaling (Sharma et al 2011; Henderson et al 2012).…”

Transcriptome analyses identify key cellular factors associated with HIV-1-associated neuropathogenesis in infected men

“…This enables infection of other CNS resident monocytic cells including microglia and perivascular macrophages [7–9]. Infiltration of monocytes into brain and associated inflammatory and metabolic toxicity is the hallmark of HAND that results in neuronal degeneration, apoptosis and associated changes [10]. HAART has drastically reduced dementia and brain pathology, however the prevalence of ANI and MND remains high in HIV-1 positive individuals [3, 4].…”