Hyperactivation of mammalian target of rapamycin complex 1 by HIV-1 is necessary for virion production and latent viral reactivation

• Verfasst von: Kumar, Binod [VerfasserIn]
• Verfasst von: Arora, Sakshi [VerfasserIn]
• Titel: Hyperactivation of mammalian target of rapamycin complex 1 by HIV-1 is necessary for virion production and latent viral reactivation
• Verf.angabe: Binod Kumar, Sakshi Arora, Shaista Ahmed, and Akhil C. Banerjea
• Jahr: 2017
• Umfang: 12 S.
• Fussnoten: Published online: 4 Oct 2016 ; Gesehen am 09.11.2018
• Titel Quelle: Enthalten in: Federation of American Societies for Experimental BiologyThe FASEB journal
• Ort Quelle: Hoboken, NJ : Wiley, 1987
• Jahr Quelle: 2017
• Band/Heft Quelle: 31(2017), 1, Seite 180-191
• ISSN Quelle: 1530-6860
• DOI: doi:10.1096/fj.201600813R
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1582752931

Abstract

Generation of new HIV-1 virions requires the constant supply of proteins, nucleotides, and energy; however, it is not known which cellular pathways are perturbed and what molecular mechanisms are employed. We hypothesized that HIV-1 may regulate pathways that control synthesis of biomolecules in the cell. In this study, we provide evidence that HIV-1 hyperactivates mammalian target of rapamycin complex 1 (mTORC1), the central regulator of biosynthesis. Mechanistically, we identify the viral regulatory gene tat (transactivator) as being responsible for increasing mTORC1 activity in a PI3K-dependent manner. Furthermore, we show that hyperactivation of mTORC1 leads to activation of the enzyme, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase, and repression of initiation factor 4E-binding protein 1 activity. These are regulators of nucleotide biogenesis and protein translation, respectively. Moreover, we are able to replicate these results in HIV-1 latent cell line models. Finally, we show that inhibition of mTORC1 or PI3K inhibits viral replication and viral reactivation as a result of a decrease in biosynthesis. Overall, our study identifies a new avenue in HIV-1 biology that can lead to development of novel therapeutic targets.