Abstract
ABSTRACTAntiviral innate host defenses against acute viral infections include suppression of host protein synthesis to restrict viral protein production. Less is known about mechanisms by which viral pathogens subvert host antiviral innate responses for establishing their replication and dissemination. We investigated early innate defense against human immunodeficiency virus (HIV) infection and viral evasion by utilizing human CD4+ T cell cultures in vitro and a simian immunodeficiency virus (SIV) model of AIDS in vivo. Our data showed that early host innate defense against the viral infection involves GCN2-ATF4 signaling-mediated suppression of global protein synthesis, which is exploited by the virus for supporting its own replication during early viral infection and dissemination in the gut mucosa. Suppression of protein synthesis and induction of protein kinase GCN2-ATF4 signaling were detected in the gut during acute SIV infection. These changes diminished during chronic viral infection. HIV replication induced by serum deprivation in CD4+ T cells was linked to the induction of ATF4 that was recruited to the HIV long terminal repeat (LTR) to promote viral transcription. Experimental inhibition of GCN2-ATF4 signaling either by a specific inhibitor or by amino acid supplementation suppressed the induction of HIV expression. Enhancing ATF4 expression through selenium administration resulted in reactivation of latent HIV in vitro as well as ex vivo in the primary CD4+ T cells isolated from patients receiving suppressive antiretroviral therapy (ART). In summary, HIV/SIV exploits the early host antiviral response through GCN2-ATF4 signaling by utilizing ATF4 for activating the viral LTR transcription to establish initial viral replication and is a potential target for HIV prevention and therapy.
Highlights
Antiviral innate host defenses against acute viral infections include suppression of host protein synthesis to restrict viral protein production
Our findings suggest that while general control nonderepressible 2 (GCN2)-ATF4 signaling is activated as a host antiviral innate defense to limit viral protein translation and infection, human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) is able to hijack GCN2-ATF4 signaling for its own replication and establishment of infection
Our findings demonstrate that HIV may exploit the host mbio.asm.org 9
Summary
Antiviral innate host defenses against acute viral infections include suppression of host protein synthesis to restrict viral protein production. 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 (eIF2␣). Despite the suppression of global protein synthesis during viral infections, a specific set of mRNAs is preferentially translated, including the transcription factor ATF4 [12] It is not known whether ATF4 expression is altered during early stages of HIV/simian immunodeficiency virus (SIV) infections and whether it activates HIV transcription. In the CD4ϩ T cells under nutrient insufficiency conditions, addition of GCN2-specific inhibitor or supplementation of amino acids to the cells resulted in the
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