Effects of HIV-1 Tat on oligodendrocyte viability are mediated by CaMKII?-GSK3? interactions.

ABSTRACT: Myelin disruptions are frequently reported in human immunodeficiency virus (HIV)-infected individuals and can occur in the CNS very early in the disease process. Immature oligodendrocytes (OLs) are quite sensitive to toxic increases in [Ca2+ ]i caused by exposure to HIV-1 Tat (transactivator of transcription, a protein essential for HIV replication and gene expression), but sensitivity to Tat-induced [Ca2+ ]i is reduced in mature OLs. Tat exposure also increased the activity of Ca2+ /calmodulin-dependent kinase II? (CaMKII?), the major isoform of CaMKII expressed by OLs, in both immature and mature OLs. Since CaMKII? is reported to interact with glycogen synthase kinase 3? (GSK3?), and GSK3? activity is implicated in OL apoptosis as well as HIV neuropathology, we hypothesized that disparate effects of Tat on OL viability with maturity might be because of an altered balance of CaMKII?-GSK3? activities. Tat expression in vivo led to increased CaMKII? and GSK3? activity in multiple brain regions in transgenic mice. In vitro, immature murine OLs expressed higher levels of GSK3?, but much lower levels of CaMKII?, than did mature OLs. Exogenous Tat up-regulated GSK3? activity in immature, but not mature, OLs. Tat-induced death of immature OLs was rescued by the GSK3? inhibitors valproic acid or SB415286, supporting involvement of GSK3? signaling. Pharmacologically inhibiting CaMKII? increased GSK3? activity in Tat-treated OLs, and genetically knocking down CaMKII? promoted death in mature OL cultures treated with Tat. Together, these results suggest that the effects of Tat on OL viability are dependent on CaMKII?-GSK3? interactions, and that increasing CaMKII? activity is a potential approach for limiting OL/myelin injury with HIV infection.

SUBMITTER: Zou S 

PROVIDER: S-EPMC6438763 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature