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

Hyperactivation of mammalian target of rapamycin complex 1 by HIV-1 is necessary for virion production and latent viral reactivation.
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Kumar B, Arora S, Ahmed S, Banerjea AC,


Kumar B, Arora S, Ahmed S, Banerjea AC, (click to view)

Kumar B, Arora S, Ahmed S, Banerjea AC,

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FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2016 Oct 4() pii

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.-Kumar, B., Arora, S., Ahmed, S., Banerjea, A. C. Hyperactivation of mammalian target of rapamycin complex 1 by HIV-1 is necessary for virion production and latent viral reactivation.

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