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

Michael R Duggan; Taha Mohseni Ahooyi; Vinay Parikh; Kamel Khalili

doi:10.1038/s41420-021-00424-0

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

Cell Death Discov. 2021 Mar 26;7(1):60. doi: 10.1038/s41420-021-00424-0.

Authors

Michael R Duggan^{1

2}, Taha Mohseni Ahooyi¹, Vinay Parikh², Kamel Khalili³

Affiliations

¹ Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, 7th Floor, Philadelphia, PA, 19140, USA.
² Department of Psychology, College of Liberal Arts at Temple University, 1701 N 13th Street, 9th Floor, Philadelphia, PA, 19122, USA.
³ Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, 7th Floor, Philadelphia, PA, 19140, USA. kamel.khalili@temple.edu.

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.

Abstract

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