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

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.

Metabolically active CD4+ T cells expressing Glut1 and OX40 preferentially harbor HIV during in vitro infection

“…Interestingly, PI3K signaling is tightly coupled to mTOR activity, recently shown to regulate HIV latency [57] and control production of pro-inflammatory cytokines from activated CD4+ T cells [58]. Indeed, inhibition of PI3K and mTOR1/2 has been shown to suppress HIV reactivation and replication, including multidrug resistant strains by reducing cellular biosynthesis [59,60]. Our findings support therapeutic targeting metabolism through the OX40-PI3Kc axis in CD4+ T cells to reduce metabolic activity necessary for HIV reactivation and homeostatic proliferation of the CD4+ T cell-restricted HIV reservoir.…”

Sugar or Fat?—Metabolic Requirements for Immunity to Viral Infections

“…This is mediated via activation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase, and repression of initiation factor 4E-binding protein 1 activity, which regulates nucleotide biogenesis and protein translation, respectively. Furthermore, inhibiting mTORC1 or PI3K inhibits viral replication and reactivation ( 89 , 90 ). In another study, rapamycin unexpectedly failed to inhibit HIV reactivation in in vitro TCR-activated resting CD4 + T cells from individuals on suppressive ART.…”

Mesenchymal stem cells are attracted to latent HIV-1-infected cells and enable virus reactivation via a non-canonical PI3K-NFκB signaling pathway

“…This quinolinone compound was also found to be a specific agonist of the PI3K p110α isoform, but not the p110β, δ or γ isoforms 54 . Another recent study by Kumar et al ., (2017) documented that the mammalian target of rapamycin complex 1 (mTORC1), which is a downstream target of PI3K and AKT, is necessary for HIV-1 production from U1 cells 55 . Indeed, similar to our findings using SC-79 (an AKT-activator), which suppressed ASC-mediated latency-reactivation; these investigators demonstrated that inhibition of mTORC1 or PI3K was able to inhibit HIV-1 reactivation as well 55 .…”

“…Another recent study by Kumar et al ., (2017) documented that the mammalian target of rapamycin complex 1 (mTORC1), which is a downstream target of PI3K and AKT, is necessary for HIV-1 production from U1 cells 55 . Indeed, similar to our findings using SC-79 (an AKT-activator), which suppressed ASC-mediated latency-reactivation; these investigators demonstrated that inhibition of mTORC1 or PI3K was able to inhibit HIV-1 reactivation as well 55 . Therefore, the crucial role of PI3K pathway, and more specifically, the cross-talk between the PI3K and NFκB pathways, should provide a novel therapeutic approach.…”