Gelsolin segment 5 inhibits HIV-induced T-cell apoptosis via Vpr-binding to VDAC

Abstract 

Viral protein R (Vpr) from the human immunodeficiency virus induces cell cycle arrest in proliferating cells, stimulates virus transcription, and regulates activation and apoptosis of infected T-lymphocytes. We report that Jurkat cells overexpressing full-length gelsolin show resistance to Vpr-induced T-cell apoptosis with abrogation of mitochondrial membrane potential loss and the release of cytochrome c. Co-immunoprecipitation assays in HEK293T cells demonstrated that overexpression of full-length or segment 5 (G5) but not G5-deleted gelsolin (ΔG5) bound to the voltage-dependent anion channel (VDAC), and that the G5 subunit can inhibit HIV-1-Vpr-binding to VDAC. We also confirmed that full-length gelsolin has the same effect in Jurkat cells. Clonogenic analysis showed that transfection of G5 but not ΔG5 cDNA protects Jurkat T cells from HIV-Vpr-Tet induced T-cell apoptosis and promoted cell survival, as did full-length gelsolin. These results suggest that the gelsolin G5 domain inhibits HIV-Vpr-induced T-cell apoptosis by blocking the interaction between Vpr and VDAC, and might be used as a protective treatment against HIV-Vpr-induced T-cell apoptosis.

Keywords: Cytoskeletal protein, AIDS, Mitochondria, Cell death

Abbreviations: HIV-1, human immunodeficiency virus type 1, Vpr, viral protein R, VDAC, voltage-dependent anion channel, MMP, mitochondrial membrane permeabilization, IB, immunoblotting, Dox, doxycycline, PTPC, permeability transition pore complex, ANT, adenine nucleotide translocator, NMDA, N-methyl-d-aspartate, VDCC, voltage-dependent calcium channels, rtTA, reverse tetracycline-controlled transactivator, PI, propidium iodide, IP, immunoprecipitation