Hyperactivation of mammalian target of rapamycin complex 1 by HIV-1 is necessary for virion production and latent viral reactivation
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...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
2017
|
| In: |
The FASEB journal
Year: 2017, Volume: 31, Issue: 1, Pages: 180-191 |
| ISSN: | 1530-6860 |
| DOI: | 10.1096/fj.201600813R |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1096/fj.201600813R Verlag, Volltext: https://www.fasebj.org/doi/10.1096/fj.201600813R 
|
| Author Notes: | Binod Kumar, Sakshi Arora, Shaista Ahmed, and Akhil C. Banerjea |
| Summary: | 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. |
|---|---|
| Item Description: | Published online: 4 Oct 2016 Gesehen am 09.11.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1530-6860 |
| DOI: | 10.1096/fj.201600813R |