Abstract
The protein kinase B or Akt is a central regulator of survival, metabolism, growth and proliferation of the cells and is known to be targeted by various viral pathogens, including HIV-1. The central role of Akt makes it a critical player in HIV-1 pathogenesis, notably by affecting viral entry, latency and reactivation, cell survival, viral spread and immune response to the infection. Several HIV proteins activate the PI3K/Akt pathway, to fuel the progression of the infection. Targeting Akt could help control HIV-1 entry, viral latency/replication, cell survival of infected cells, HIV spread from cell-to-cell, and the immune microenvironment which could ultimately allow to curtail the size of the HIV reservoir. Beside the “shock and kill” and “block and lock” strategies, the use of Akt inhibitors in combination with latency inducing agents, could favor the clearance of infected cells and be part of new therapeutic strategies with the goal to “block and clear” HIV.
Highlights
The protein kinase B or Akt is a central regulator of survival, metabolism, growth and proliferation of the cells (Malim and Emerman, 2008) and is known to be targeted by various viral pathogens, including HIV-1 (Diehl and Schaal, 2013)
The phosphoinositide 3-kinase (PI3K)/Akt pathway is involved in several key cellular processes that are involved in the progression of HIV-1 pathogenesis (Fayard et al, 2010)
Due to its critical role in HIV pathogenesis, targeting PI3K/Akt pathway could control HIV-1 entry, viral latency/replication, cell survival of infected cells, HIV spread from cell-to-cell, and the immune microenvironment which could allow to curtail the size of the HIV reservoir
Summary
The protein kinase B or Akt is a central regulator of survival, metabolism, growth and proliferation of the cells (Malim and Emerman, 2008) and is known to be targeted by various viral pathogens, including HIV-1 (Diehl and Schaal, 2013). HIV infection is characterized by a latency phase and the presence of long-lived cellular reservoirs, from which viral reactivation occurs The establishment of these viral reservoirs requires the regulation of cellular pathways activation to induce transcriptional silencing of the viral genome, and the enhancement of cell survival, notably by reducing the stressinduced apoptosis. HIV-1 protein Nef activates the PI3K/Akt pathway and downregulates the inhibitor protein PTEN This Akt activation, coupled with the induction of miR718, results in the alteration of the phosphorylation pattern of serine rich proteins involved in the regulation of translation. HIV-1 reactivation is induced by extracellular vesicles, notably exosomes, from uninfected cells, regardless of treatment This extracellular activation is driven via the PI3K/Akt pathway (Barclay et al, 2020)
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