Defining the molecular mechanisms of HIV‐1 Tat secretion: PtdIns(4, 5)P2 at the epicenter. (13th July 2018)

• Record Type: Journal Article
• Authors: Mele, Anthony R; Marino, Jamie; Chen, Kenneth; Pirrone, Vanessa; Janetopoulos, Chris; Wigdahl, Brian; Klase, Zachary; Nonnemacher, Michael R
• Is Part Of: Traffic. Volume 19:Number 9(2018)
• Page Start: 655
• Page End: 665
• Publication Date: 2018-07-13
• Subjects: astrocyte -- exosome -- HIV‐1 -- monocyte‐macrophage -- PtdIns(4, 5)P2 -- secretion -- Tat -- T‐cell; Biological transport -- Periodicals; 571.6
• DOI: 10.1111/tra.12578
• Languages: English
• ISSNs: 1398-9219

Abstract

Abstract : The human immunodeficiency virus type 1 (HIV‐1) transactivator of transcription (Tat) protein functions both intracellularly and extracellularly. Intracellularly, the main function is to enhance transcription of the viral promoter. However, this process only requires a small amount of intracellular Tat. The majority of Tat is secreted through an unconventional mechanism by binding to phosphatidylinositol‐4, 5‐bisphosphate (PtdIns(4, 5)P2 ), a phospholipid in the inner leaflet of the plasma membrane that is required for secretion. This interaction is mediated by the basic domain of Tat (residues 48‐57) and a conserved tryptophan (residue 11). After binding to PtdIns(4, 5)P2, Tat secretion diverges into multiple pathways, which we categorized as oligomerization‐mediated pore formation, spontaneous translocation and incorporation into exosomes. Extracellular Tat has been shown to be neurotoxic and toxic to other cells of the central nervous system (CNS) and periphery, able to recruit immune cells to the CNS and cerebrospinal fluid, and alter the gene expression and morphology of uninfected cells. The effects of extracellular Tat have been examined in HIV‐1‐associated neurocognitive disorders (HAND); however, only a small number of studies have focused on the mechanisms underlying Tat secretion. In this review, the molecular mechanisms of Tat secretion will be examined in a variety of biologically relevant cell types. Abstract : The HIV‐1 transactivator of transcription (Tat) protein causes a myriad of effects to bystander cells, such as apoptosis and gene expression alterations, once secreted from infected cells. Tat is accepted as a crucial component of HIV‐1‐associated neurocognitive disorders (HAND) by causing neurotoxicity within the CNS. The mechanisms associated with Tat secretion are still poorly understood. This review examines gaps in published knowledge and uses existing evidence to categorize the mechanisms of secretion and their relevance to cells influenced during HAND.