HCMV modulation of cellular PI3K/AKT/mTOR signaling: New opportunities for therapeutic intervention?

Abstract

Human cytomegalovirus (HCMV) remains a major public health burden domestically and abroad. Current approved therapies, including ganciclovir, are only moderately efficacious, with many transplant patients suffering from a variety of side effects. A major impediment to the efficacy of current anti-HCMV drugs is their antiviral effects are restricted to the lytic stage of viral replication. Consequently, the non-lytic stages of the viral lifecycle remain major sources of HCMV infection associated with transplant recipients and ultimately the cause morbidity and mortality. While work continues on new antivirals that block lytic replication, the dormant stages of HCMV's unique lifecycle need to be concurrently assessed for new therapeutic interventions. In this review, we will examine the role that the PI3K/Akt/mTOR signaling axis plays during the different stages of HCMV's lifecycle, and describe the advantages of targeting this cellular pathway as an antiviral strategy. In particular, we focus on the potential of exploiting the unique modifications HCMV imparts on the PI3K/Akt/mTOR pathway during quiescent infection of monocytes, which serve an essential role in the viral dissemination strategy of the virus.

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

“…The virus engages various cellular entry receptors, several of which activate similar pathways relevant to the IE phase of infection [145][146][147][148][149]. In particular, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor alpha and integrins independently trigger the phosphatidylinositol 3-phosphate and protein kinase B (PI3K/AKT) pathway [150][151][152]. The PI3K/AKT pathway is central to many cellular properties including motility, proliferation and survival [153][154][155].…”

Targeting cancer stem cells in drug discovery: Current state and future perspectives

“…BMP, an important member of the transforming growth factor-β (TGF-β) family, represents a class of secreted glycoproteins that induce ectopic bone and cartilage formation, and it is involved in many important biological processes, such as embryonic development, cell differentiation, and organ formation[129]. BMP-7 has been shown to reduce macrophage infiltration and tissue damage in animal models of acute and chronic renal failure[130]. BMP-7 was originally approved in 2001 for the treatment of the nonunion of long bone fractures secondary to trauma, and it has also been studied in phase II/III trials for the treatment of periodontal disease.…”

“…The PI3K/Akt signaling pathway is both a convergence and divergence point for many cell signals that regulate the phosphorylation of signaling molecules, and this pathway engages in crosstalk with the BMP/Smad and Wnt/β-catenin pathways, among others. Then, downstream signaling affects the expression of nuclear transcription factors, ultimately regulating cell proliferation, self-renewal, and multidirectional differentiation potential[130,131]. GDC-0084 (Figure 5), a small molecule inhibitor of the PI3K/AKT/mTOR pathway, is being studied in a phase II clinical trial for the treatment of glioblastoma multiforme (GBM).…”

Metabolomic Profile of Posner–Schlossman Syndrome: A Gas Chromatography Time-of-Flight Mass Spectrometry-Based Approach Using Aqueous Humor

“…Moreover, BCAAs have been widely known to activate mammalian target of rapamycin (mTOR), which can modulate autophagy and inflammatory responses (Xu and Brink, 2016; Saxton and Sabatini, 2017; Sinclair et al, 2017). Reports have demonstrated that mTOR can facilitate PI3K/Akt-induced NF-κB activation (Peppenelli et al, 2018; Altman et al, 2019), an important step in all the three stages of HCMV infection (Li et al, 2015; Peppenelli et al, 2018; Altman et al, 2019) (). Consequently, targeting the PIK/Akt/mTOR cascade might be more efficient for treating HCMV-positive PSS.…”