Neuromodulation of BAG co-chaperones by HIV-1 viral proteins and H2O2: implications for HIV-associated neurological disorders

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.

HIV Nef Expression Down-modulated GFAP Expression and Altered Glutamate Uptake and Release and Proliferation in Astrocytes

“…NeuroHIV remains highly prevalent among the HIVinfected population, yet its exact cause evades full understanding with no effective therapeutics available. HIV infection of astrocytes and subsequent dysregulation of astrocyte function are known to contribute to the disease [40,[68][69][70]. With GFAP being a major astrocytic protein involved in maintaining physiological homeostasis of astrocytes, we chose to determine if and how Nef might influence GFAP expression, possibly leading to astrocyte dysfunction.…”

Role of BAG5 in Protein Quality Control: Double-Edged Sword?

“…Interestingly, among all the members of the family, BAG5 has drawn considerable attention as it is expressed in the cardiomyocytes ( Gupta et al, 2016 ) and plays a pivotal role in monitoring cell homeostasis under stressful conditions ( Gupta et al, 2016 ; Duggan et al, 2021 ). In fact, studies have indicated that BAG5 protein overexpression can limit oxidative stress and mitochondrial dysfunction in the cells ( Wang et al, 2014 ; Gupta et al, 2016 ).…”

“…The role of BAG5 as a stress regulator is further substantiated by a very recent study which revealed that exposure of primary neuronal cultures to H 2 O 2 for 6 h induced oxidative stress. Also, this was accompanied by a reduction in the expression of BAG5 protein ( Duggan et al, 2021 ). This indicates that stressful conditions downregulate BAG5 expression and induce cell death.…”