Efavirenz Promotes β-Secretase Expression and Increased Aβ1-40,42 via Oxidative Stress and Reduced Microglial Phagocytosis: Implications for HIV Associated Neurocognitive Disorders (HAND)

Abstract

Efavirenz (EFV) is among the most commonly used antiretroviral drugs globally, causes neurological symptoms that interfere with adherence and reduce tolerability, and may have central nervous system (CNS) effects that contribute in part to HIV associated neurocognitive disorders (HAND) in patients on combination antiretroviral therapy (cART). Thus we evaluated a commonly used EFV containing regimen: EFV/zidovudine (AZT)/lamivudine (3TC) in murine N2a cells transfected with the human “Swedish” mutant form of amyloid precursor protein (SweAPP N2a cells) to assess for promotion of amyloid-beta (Aβ) production. Treatment with EFV or the EFV containing regimen generated significantly increased soluble amyloid beta (Aβ), and promoted increased β-secretase-1 (BACE-1) expression while 3TC, AZT, or, vehicle control did not significantly alter these endpoints. Further, EFV or the EFV containing regimen promoted significantly more mitochondrial stress in SweAPP N2a cells as compared to 3TC, AZT, or vehicle control. We next tested the EFV containing regimen in Aβ - producing Tg2576 mice combined or singly using clinically relevant doses. EFV or the EFV containing regimen promoted significantly more BACE-1 expression and soluble Aβ generation while 3TC, AZT, or vehicle control did not. Finally, microglial Aβ phagocytosis was significantly reduced by EFV or the EFV containing regimen but not by AZT, 3TC, or vehicle control alone. These data suggest the majority of Aβ promoting effects of this cART regimen are dependent upon EFV as it promotes both increased production, and decreased clearance of Aβ peptide.

Antiretrovirals, Methamphetamine, and HIV-1 Envelope Protein gp120 Compromise Neuronal Energy Homeostasis in Association with Various Degrees of Synaptic and Neuritic Damage

“…Furthermore, similar to HIV-1 gp120, the earliest antiretroviral drug, AZT, has been shown to impair neurogenesis (79-81), besides affecting cerebrocortical mitochondria (82). Efavirenz (EFV) and NVP, which are currently FDA approved and used in NNRTI regimens (http://aidsinfo.nih.gov/guidelines), have been suggested to exert neurotoxicity (14,62,83). One study found that EFV caused a loss of ATP, depolarization and fragmentation of mitochondria, and increased mitophagy and autophagy, in general, in neuron-like SHSY-5Y cells and primary rat striatal neurons, suggesting a disturbance of energy homeostasis as a mechanism of toxicity (84).…”

Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients

“…The biological mechanisms that might underlie worse neurocognitive performance in EFV users are not known but may be caused by neurotoxicity of EFV metabolites, 7-OH-EFV and 8-OH-EFV, producing morphological damage to dendritic spines in vitro (Tovar-y-Romo et al 2012), which suggests potential synergy with synaptodendritic pathology that occurs in HIV-associated dementia and HAND (Ellis et al 2007; Kaul et al 2001). More recent studies also suggest an important role of EFV-induced oxidative stress and the increase of amyloid-beta production in its neurotoxicity (Brown et al 2014). In contrast to EFV neurotoxicity, few investigations have focused on the possible neurotoxicity of LPV/r.…”

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

“…Nucleoside reverse transcriptase inhibitors have been reported to reduce neuronal axon length [79, 80] and mitochondrial DNA content [81, 82]. Recently, efavirenz which was found to promote amyloid-β (Aβ) production in vitro and in vivo [83], abrogate neural stem cell proliferation [84],and alter mitochondrial dynamics(i.e., increased mitochondrial depolarization, decreased mitochondrial DNA, and altered mitochondrial respiratory function) [81, 85, 86]. In addition, raltegravir was shown to enhance IL-8 production, providing further evidence for cART-mediated neurotoxicity [87].…”

“…In another study, Brown et al [83] found that efavirenz, in combination with lamivudine and zidovudine, induces mitochondrial dysfunction as evidenced by reduced cellular ATP stores, diminished mitochondrial membrane potential, and enhanced release of ROS in SweAβPP N2a neurons. Also, efavirenz increases Aβ production via BACE1 activation in vitro and in vivo .…”