HIV Tat-mediated altered oligodendrocyte maturation involves autophagy-lysosomal dysfunction

Abstract

Abstract Objectives The current study was undertaken to understand the underlying molecular mechanism(s) by which HIV Transactivator of transcription (Tat) alters oligodendrocyte maturation through the generation of reactive oxygen species (ROS), impairment of lysosomal functioning, and dysregulation of autophagy. Methods We exposed primary rat immature oligodendrocytes to HIV Tat and utilized various experimental techniques to assess its effects on oligodendrocytes maturation. We measured ROS levels, assessed lysosomal membrane potential, determined cathepsin D activity, and analyzed the expression of autophagy-related markers. Furthermore, we investigated the potential of ROS scavengers and lysosomal protectants to mitigate the damaging effects of HIV Tat on oligodendrocytes maturation. Results Exposure of primary rat immature oligodendrocytes to HIV Tat significantly increased ROS levels, indicating the induction of oxidative stress. This oxidative stress impaired lysosomal functioning, as evidenced by a substantial increase in lysosomal membrane potential and a decrease in cathepsin D activity. Compromised lysosomal function resulted in dysregulated autophagy, which was confirmed by increased expression of SQSTM1. However, the administration of ROS scavengers and lysosomal protectants effectively attenuated the detrimental effects of HIV Tat on oligodendrocytes maturation. Conclusions Our findings demonstrate that HIV Tat exposure induces oxidative stress, impairs lysosomal functioning, and dysregulates autophagy in oligodendrocytes. These molecular changes likely contribute to the altered maturation of oligodendrocytes observed in HIV-infected individuals. Understanding these underlying mechanisms provides valuable insights into the pathogenesis of HIV-associated neurocognitive disorders and highlights the potential of therapeutic strategies targeting ROS scavenging and lysosomal protection as adjunctive approaches for managing such complications in HIV +ve individuals.