ReviewPost-screenmTOR as a multifunctional therapeutic target in HIV infection
Section snippets
mTOR and its pharmacological inhibitors: multifunctional agonists and antagonists regulating immune functions, cancer, aging, viral infection and autism spectrum disorders
The mammalian target of rapamycin (mTOR), also known as mechanistic target of rapamycin or FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a ∼289 kDa protein originally discovered and cloned from Saccharomyces cerevisiae that shares sequence homologies with the phosphoinositide 3-kinase (PI3-kinase) family and represents a serine/threonine protein kinase that is present in all eukaryotic organisms [1].
mTOR plays a key part as an intracellular nutrient sensor that controls
HIV and its treatment: advantages and some limits of HAART
HIV is a genetically related member of the Lentivirus genus of the Retroviridae family that shows a particular tropism for CD4+ T cells [15]. However, the CD4 antigen alone is not sufficient for virus entry, because a co-receptor is necessary to gain access into the cells. These molecules belong to the family of seven-transmembrane domain G-protein-coupled receptors. Typically, CXCR4 is used by strains with tropism for T cells and CCR5 by strains with tropism for macrophages [16].
The course of
mTOR and CD4+-T-cell loss
mTOR activation seems to play a pathogenetic part in the dysregulated apoptosis of CD4+ T cells in HIV-1 patients through gp120-mediated activation of the CD4/CXCR4 (or CCR5)/mTOR/p53 axis [24]. In fact, mTOR can phosphorylate p53 on serine 15 involved in Env-induced syncytial apoptosis [25]. The complex of the Env glycoprotein expressed on the membrane of HIV-1-infected cells can also induce apoptosis of uninfected cells expressing CD4 and CXCR4 or CCR5 through interaction between
Concluding remarks
The data discussed indicate that hyperactivation of mTOR occurs in different pathologies associated with HIV infection such as nephropathy and AIDS-associated and non-AIDS-associated malignancies. Hyperactivation of mTOR could also be responsible for defective autophagy that can contribute to the pathogenesis of neurocognitive disorders during HIV infection (Fig. 2). Preclinical evidence indicates that selective inhibitors of mTOR such as rapamycin could represent a novel therapeutic approach
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2022, Blood ReviewsCitation Excerpt :In various HIV-1 latency models and HIV-infected patient cells, the reversal of HIV latency can be suppressed by the knockdown of mTOR complex subunits and the pharmacological inhibition of mTOR activity [82]. The hyperactivation of mTOR contributes to the dysregulation of apoptosis and autophagy, thereby reducing CD4+ T-cell loss, dysfunction of innate immunity, and development of neurocognitive disorders.[83] Thus, designing PI3K-mTOR and PI3K-mTOR-bromodomain 4 (BRD4) inhibitors, where BRD4 inhibitors can induce the activation of latent viruses and where PI3K/mTOR inhibitors can induce autophagy, could be an effective strategy to eradicate HIV-infected T cells or macrophages.[84].
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