Abstract
Despite increasing numbers of aged individuals living with HIV, the mechanisms underlying HIV-associated neurological disorders (HANDs) remain elusive. As HIV-1 pathogenesis and aging are characterized by oxidative stress as well as altered protein quality control (PQC), reactive oxygen species (ROS) themselves might constitute a molecular mediator of neuronal PQC by modulating BCL-2 associated athanogene (BAG) family members. Present results reveal H2O2 replicated and exacerbated a reduction in neuronal BAG3 induced by the expression of HIV-1 viral proteins (i.e., Tat and Nef), while also causing an upregulation of BAG1. Such a reciprocal regulation of BAG3 and BAG1 levels was also indicated in two animal models of HIV, the doxycycline-inducible Tat (iTat) and the Tg26 mouse. Inhibiting oxidative stress via antioxidants in primary culture was capable of partially preserving neuronal BAG3 levels as well as electrophysiological functioning otherwise altered by HIV-1 viral proteins. Current findings indicate HIV-1 viral proteins and H2O2 may mediate neuronal PQC by exerting synergistic effects on complementary BAG family members, and suggest novel therapeutic targets for the aging HIV-1 population.
Highlights
Introduction Amongst persons living withHIV, the implementation of combined antiretroviral therapies since the mid-1990s has significantly increased life expectancies and decreased mortality rates such that approximately half of the HIV+ population is ≥50 years of age[1]
Initial findings indicate the viral proteins Tat and negative factor (Nef) are capable of inducing oxidative stress in neurons, while concomitantly mitigating BAG3 levels
The current findings address the potential for HIV-1 viral proteins and H2O2 to induce variation in neuronal BCL-2 associated athanogene (BAG) family members, a family of proteins responsible for efficient protein quality control (PQC)
Summary
HIV, the implementation of combined antiretroviral therapies (cARTs) since the mid-1990s has significantly increased life expectancies and decreased mortality rates such that approximately half of the HIV+ population is ≥50 years of age[1]. This cohort is consistently found to be at a significantly greater risk for developing HIV-associated neurological disorders (HANDs), a spectrum of cognitive deficits reflecting impairments across several domains (e.g., executive functioning, memory, attention) and ensuing detriments on daily functioning[2,3,4,5,6]. Consistent with the effect of Tat, Official journal of the Cell Death Differentiation Association
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