Activation of GCN2 upon HIV-1 infection and inhibition of translation

Abstract

Higher eukaryotic organisms have a variety of specific and nonspecific defense mechanisms against viral invaders. In animal cells, viral replication may be limited through the decrease in translation. Some viruses, however, have evolved mechanisms that counteract the response of the host. We report that infection by HIV-1 triggers acute decrease in translation. The human protein kinase GCN2 (eIF2AK4) is activated by phosphorylation upon HIV-1 infection in the hours following infection. Thus, infection by HIV-1 constitutes a stress that leads to the activation of GCN2 with a resulting decrease in protein synthesis. We have shown that GCN2 interacts with HIV-1 integrase (IN). Transfection of IN in amino acid-starved cells, where GCN2 is activated, increases the protein synthesis level. These results point to an as yet unknown role of GCN2 as an early mediator in the cellular response to HIV-1 infection, and suggest that the virus is able to overcome the involvement of GCN2 in the cellular response by eliciting methods to maintain protein synthesis.

GCN2 phosphorylates HIV-1 integrase and decreases HIV-1 replication by limiting viral integration

“…Interestingly, we found GCN2 to be activated upon HIV-1 infection which, in turn, decreased HIV-1 replication 7, 8 . This protein kinase is conserved from yeast to human and is part of the four eIF2α’s kinases found in mammalian cells along with PERK, PKR and HRI.…”

HIV-1 translation and its regulation by cellular factors PKR and PACT

“…For HIV-1, this block can be alleviated by the TAR RNA Binding protein (TRBP), by the autoantigen La, by Staufen or by DEAD box polypeptide 3 (DDX3) Dorin et al, 2003;Dugré-Brisson et al, 2005;Soto-Rifo et al, 2012b;Svitkin et al, 1994), but these factors have not been studied in the context of HIV-2 for which the IRES may play an important function (Soto-Rifo et al, 2012a). Furthermore, the cellular proteins, PKR, 5 OAS, Schlafen and GCN2 negatively impact HIV-1 translation in response to IFN, stress and dsRNA Cosnefroy et al, 2013;del Pino et al, 2012;Jakobsen et al, 2013;Li et al, 2012;Silverman, 2007). In contrast, cellular factors such as the RNA helicase A (RHA), upframeshift protein 1 and the Rev co-factors Sam68, eIF5A, human Rev-interacting protein (hRIP) and DDX3 increase cap-dependent translation efficiency of HIV-1, although eIF5A, hRIP and DDX3 also act on IRES-mediated translation (Ajamian et al, 2008;Bolinger et al, 2010;Liu et al, 2011;Soto-Rifo et al, 2012b).…”

HIV Exploits Antiviral Host Innate GCN2-ATF4 Signaling for Establishing Viral Replication Early in Infection

“…It has been well established that acute viral infections activate an antiviral response in host cells that includes inhibition of protein synthesis and amino acid deprivation (10). This leads to the restriction of the viral protein production and results in the control of the viral infection through the mechanism of phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α).…”

“…This leads to the restriction of the viral protein production and results in the control of the viral infection through the mechanism of phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). HIV infection of cell lines in vitro induced inhibition of protein translation and increased expression of the protein kinase general control nonderepressible 2 (GCN2) (10). Phosphorylation of eIF2α by activated GCN2 converts eIF2 to a competitive inhibitor of eIF2B and results in the inhibition of protein synthesis (11).…”

“…The SIV model of AIDS has been valuable for unraveling the mechanisms of HIV pathogenesis. A combination of the SIV model and well-established HIV cell culture systems in vitro provides an excellent opportunity to interrogate early stages of viral infection in the context of host antiviral innate defense and mechanisms of viral evasion or exploitation of the host antiviral pathways for establishing early viral reservoirs (10, 13–16). …”