Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders

Abstract

Despite effective viral suppression through combined antiretroviral therapy (cART), approximately half of HIV-positive individuals suffer from HIV-Associated Neurocognitive Disorders (HAND). Studies of antiretroviral treated patients have revealed persistent white matter pathologies including diffuse myelin pallor, diminished white matter tracts, and decreased myelin protein mRNAs. Loss of myelin can contribute to neurocognitive dysfunction as the myelin membrane generated by oligodendrocytes is essential for rapid signal transduction and axonal maintenance. We hypothesized that myelin changes in HAND are partly due to effects of antiretroviral drugs on oligodendrocyte survival and/or maturation. We showed that primary mouse oligodendrocyte precursor cell cultures treated with therapeutic concentrations of HIV protease inhibitors Ritonavir or Lopinavir displayed dose-dependent decreases in oligodendrocyte maturation; however, this effect was rapidly reversed following drug removal. Conversely, nucleoside reverse transcriptase inhibitor Zidovudine had no effect. Furthermore, in vivo Ritonavir administration to adult mice reduced frontal cortex myelin protein levels. Finally, prefrontal cortex tissue from HIV-positive individuals with HAND on cART showed a significant decrease in myelin basic protein compared with untreated HIV-positive individuals with HAND or HIV-negative controls. These findings demonstrate that antiretrovirals can impact myelin integrity, and have implications for myelination in juvenile HIV patients, and myelin maintenance in adults on lifelong therapy.

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

“…Based on neuropathological data [11, 205], genetic screening [206, 207], and CSF markers [208], researchers have raised the possibility that AD may be becoming more common in HIV patients on cART. Although the exact mechanisms through which cART contributes to Aβ deposition in the brain are unknown, neurotoxic effects of ART drugs such as mitochondrial dysfunction [81, 91, 209], increased oxidative and ER stress [82, 92, 93, 210, 211], and neuronal damage and synaptic loss [212, 213] are now linked to altered AβPP processing and Aβ deposition in the brains of HIV patients.…”

Effects of HIV‐1 Tat on oligodendrocyte viability are mediated by CaMKIIβ–GSK3β interactions

“…White matter injuries, such as decreased volume (Sarma et al 2014), increased occurrence of abnormal myelinated tracts (Gongvatana et al 2009), anddegenerated OLs (Gyorkey et al 1987;Jayadev et al 2007), contribute to HAND pathogenesis and can occur during early, asymptomatic stages of HIV infection. cART itself has also been recently shown to impact myelin integrity and maintenance (Jensen et al 2015), suggesting that these injuries may be extremely difficult to prevent in HIV-infected patients. Thus, the ability of immature OLs to survive, differentiate, and remyelinate may be an important factor in limiting CNS damage because of HIV exposure.…”

Reduced sterol regulatory element‐binding protein (SREBP) processing through site‐1 protease (S1P) inhibition alters oligodendrocyte differentiation in vitro

“…; Jensen et al . ) Briefly, the tissue was minced, triturated in 0.3% trypsin (Life Technologies, Grand Island, NY, USA) at 37°C before 10% fetal bovine serum was added, and centrifuged at 200 g for 4 min. The supernatant was removed, Neurobasal medium (NBM; Life Technologies) supplemented with B27 containing 0.5 mM L‐glutamine and 5000 U/mL Penicillin/Streptomycin was added, and the tissue dissociated by trituration.…”