mTOR as a multifunctional therapeutic target in HIV infection

HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms

“…The network representation of Akt/PI3K pathways, previously linked to Th17 lineage polarization (58-60) and reported to be upregulated in human lamina propria T cells (73), pointed to the upregulation of mTOR, a metabolic sensor involved in the regulation of numerous cellular functions via the formation of two different signaling complexes, mTORC1 and mTORC2 (74)(75)(76)(77). Considering the documented role of mTOR-mediated processes in the positive regulation of HIV replication (62,78), we proceeded to the validation of mTOR expression at protein and mRNA levels as well as functional validations in cells from the blood and/or colons of HIV-infected individuals receiving ART and uninfected study participants.…”

“…Thus, mTOR favors HIV replication/reactivation only within the unique transcriptional context of ATRA-exposed CCR6 + T cells. Evidence exists in the literature that mTOR regulates HIV replication via multiple mechanisms (78,79). One possible mechanism is via the regulation of CCR5 expression (62).…”

Anticancer activity of 23,24-dihydrocucurbitacin B against the HeLa human cervical cell line is due to apoptosis and G2/M cell cycle arrest

“…Furthermore, dysregulated mTOR stimulation has also been reported to serve a key part in the development of nephropathy and the pathogenesis of HIV-associated malignancies (27). Therefore, the role of mTOR in the pathogenesis of HIV-associated disorders and cancer suggests that the use of specific P13K/AKT/mTOR inhibitors may be a novel approach to prevent and treat these diseases (27,28). 23,24-dihydrocucurbitacin B inhibits this pathway; therefore, it may be effective at preventing the progression of diseases in which mTOR is upregulated.…”

HIV-1 Exploits Cellular miR-2909 RNomics to Initiate and Ensure AIDS Disease

“…Several pieces of evidence support the view that p53 protein controls the activity of mammalian target of rapamycin (mTOR) which is a highly conserved serine/threonine kinase recognized to play crucial role in cell homeostasis, regulation of cell growth, metabolism and autophagy in response to the environmental stress [5]. The relevance of mTOR pathway governed autophagic process, assumes importance because its deregulation is observed in several viral diseases including that in AIDS disease [6]. The mTOR has evolved to participate in two distinct functional complexes, mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2).…”

“…Because mTORC1 inhibits autophagy to end in cell death and mTORC2 promotes cell survival [7], this phenomenon makes the net contribution of mTOR-pathway to the mechanism of CD4 + T-cell depletion apparently more complex to decipher. This view is supported by the in vivo evidence that mTOR blockade with rapamycin does not influence HIV-1 induced CD4 + T-cell death [6]. However, this finding does not rule out the fact that HIV-1 infected cell induced depletion of the bystander uninfected CD4 + T-cells, may be mediated through p53-induced apoptotic pathway involving Puma and Bax [3,4] within CD4 + T-cells.…”