HIV-1 requires Staufen1 to dissociate stress granules and to produce infectious viral particles

Rao, Shringar; Hassine, Sami; Monette, Anne; Amorim, Raquel Beltrão; DesGroseillers, Luc; Mouland, Andrew J.

doi:10.1261/rna.069351.118

Cited by 31 publications

(39 citation statements)

References 42 publications

(76 reference statements)

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“…For example, knockout studies by the Sandmeyer group demonstrated that RNA granule proteins are required for Ty3 retrotransposition in yeast and likely act during assembly (48–50). Additionally the Linial group found that the RNA granule protein DDX6 is required for foamy virus packaging (51), and the Mouland group showed that the RNA granule protein Stau1 plays an important role in HIV-1 Gag assembly and packaging (52–55). Finally, the Kewalramani and Pathak groups demonstrated that RNA granule protein MOV10 influences immature HIV-1 assembly (56, 57).…”

Section: Discussionmentioning

confidence: 99%

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

Reed

Solas²,

Kitaygorodskyy³

et al. 2020

Preprint

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Given the projected increase in multidrug resistant HIV-1, there is an urgent need for development of antiretrovirals that act on virus life-cycle stages that are not targeted by antiretrovirals currently in use. Host-targeting drugs are of particular interest because they can offer a high barrier to resistance. Here we report identification of two related small molecules that inhibit HIV-1 late events, a stage of the HIV-1 life cycle for which potent and specific inhibitors are lacking. This chemotype was discovered using cell-free protein synthesis and assembly systems that recapitulate intracellular host-catalyzed viral capsid assembly pathways. These compounds inhibit replication of HIV-1 in human T cell lines and PBMCs and are effective against a primary isolate. They reduce virus production, likely by inhibiting a post-translational step in HIV-1 Gag assembly. Notably, the compound colocalizes with HIV-1 Gag in situ; however, unexpectedly, selection experiments failed to identify compound-specific resistance mutations in gag or pol, even though known resistance mutations developed in a parallel nelfinavir selection. Thus, we hypothesized that instead of binding to Gag directly, these compounds might localize to assembly intermediates, the intracellular multiprotein complexes containing Gag and host factors that are formed during immature HIV-1 capsid assembly. Indeed, imaging of infected cells showed colocalization of the compound with two host enzymes found in assembly intermediates, ABCE1 and DDX6. While the exact target and mechanism of action of this chemotype remain to be determined, these findings suggest that these compounds represent first-in-class, host-targeting inhibitors of intracellular events in HIV-1 assembly.IMPORTANCEThe success of antiretroviral treatment for HIV-1 is at risk of being undermined by the growing problem of drug resistance. Thus, there is a need to identify antiretrovirals that act on viral life cycle stages not targeted by drugs in use, such as the events of HIV-1 Gag assembly. To address this gap, we developed a compound screen that recapitulates the intracellular events of HIV-1 assembly, including viral-host interactions that promote assembly. This effort led to identification of a new chemotype that inhibits HIV-1 replication at nanomolar concentrations by inhibiting virus production. This compound colocalized with Gag and two host enzymes that facilitate capsid assembly but resistance selection did not result in compound-specific mutations in gag, suggesting that the chemotype does not directly target Gag. We hypothesize that this chemotype may represent a first-in-class inhibitor of virus production that acts by targeting a viral-host complex important for HIV-1 Gag assembly.

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Section: Discussionmentioning

confidence: 99%

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

Reed

Solas²,

Kitaygorodskyy³

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Repressing the SG response is a strategy that viruses apply to facilitate their replication. Retroviruses, such as HIV-1, can disassociate SGs to allow the production of infectious viral particles (28). However, it is still unknown whether autophagy is a strategy that viruses apply to clear SGs.…”

Section: Resultsmentioning

confidence: 99%

The Late Domain of Prototype Foamy Virus Gag Facilitates Autophagic Clearance of Stress Granules by Promoting Amphisome Formation

Zheng

Zhu²,

Yan

et al. 2020

J Virol

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Prototype foamy virus (PFV), a complex retrovirus belonging to Spumaretrovirinae, maintains lifelong latent infection. The maintenance of lifelong latent infection by viruses relies on the repression of the type I interferon (IFN) response. However, the mechanism involving PFV latency, especially regarding the suppression of the IFN response, is poorly understood. Our previous study showed that PFV promotes autophagic flux. However, the underlying mechanism and the role of PFV-induced autophagy in latent infection have not been clarified. Here, we report that the PFV viral structural protein Gag induced amphisome formation and triggered autophagic clearance of stress granules (SGs) to attenuate type I IFN production. Moreover, the late domain (L-domain) of Gag played a central role in Alix recruitment, which promoted endosomal sorting complex required for transport I (ESCRT-I) formation and amphisome accumulation by facilitating late endosome formation. Our data suggest that PFV Gag represses the host IFN response through autophagic clearance of SGs by activating the endosome-autophagy pathway. More importantly, we found a novel mechanism by which a retrovirus inhibits the SG response to repress the type I IFN response. IMPORTANCE Maintenance of lifelong latent infection for viruses relies on repression of the type I IFN response. Autophagy plays a double-edged sword in antiviral immunity. However, the role of autophagy in the regulation of the type I IFN response and the mechanism involving virus-promoted autophagy have not been fully elucidated. SGs are an immune complex associated with the antiviral immune response and are critical for type I IFN production. Autophagic clearance of SGs is one means of degradation of SGs and is associated with regulation of immunity, but the detailed mechanism remains unclear. In this article, we demonstrate that PFV Gag recruits ESCRT-I to facilitate amphisome formation. Our data also suggest that amphisome formation is a critical event for autophagic clearance of SGs and repression of the type I IFN response. More importantly, we found a novel mechanism by which a retrovirus inhibits the SG response to repress the type I IFN response.

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“…Similarly, the Theiler's murine encephalomyelitis virus (TMEV) and FMDV L proteins can inhibit SG formation [113,120]. Recent studies have shown that the picornavirus L and 2A proteins can interfere with Interferes with the eIF4GI-G3BP1 interaction [114] HPIV3 Hides viral RNA [115] HIV-1 Inhibits PKR and eIF2α phosphorylation [116,117] the eIF4GI-G3BP1 interaction and block typical SG formation [114]. In addition, EMCV and poliovirus (PV) can inhibit SG formation by 3C-mediated cleavage of G3BP1 [58,112].…”

Section: Effect Of Eif2α Phosphorylation On Viral Replication Eif2α Pmentioning

confidence: 99%

“…Moreover, viruses reduce eIF2α phosphorylation. The HIV-1 nucleocapsid (NC) interacts with the host dsRNA-binding protein Staufen1 to inhibit PKR and eIF2α phosphorylation, thereby dissociating SGs and relieving translation shutdown to achieve viral production [116,117].…”

Section: Effect Of Eif2α Phosphorylation On Viral Replication Eif2α Pmentioning

confidence: 99%

The role of host eIF2α in viral infection

Liu¹,

Wang²,

Cheng³

et al. 2020

Virol J

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Background eIF2α is a regulatory node that controls protein synthesis initiation by its phosphorylation or dephosphorylation. General control nonderepressible-2 (GCN2), protein kinase R-like endoplasmic reticulum kinase (PERK), double-stranded RNA (dsRNA)-dependent protein kinase (PKR) and heme-regulated inhibitor (HRI) are four kinases that regulate eIF2α phosphorylation. Main body In the viral infection process, dsRNA or viral proteins produced by viral proliferation activate different eIF2α kinases, resulting in eIF2α phosphorylation, which hinders ternary tRNAMet-GTP-eIF2 complex formation and inhibits host or viral protein synthesis. The stalled messenger ribonucleoprotein (mRNP) complex aggregates under viral infection stress to form stress granules (SGs), which encapsulate viral RNA and transcription- and translation-related proteins, thereby limiting virus proliferation. However, many viruses have evolved a corresponding escape mechanism to synthesize their own proteins in the event of host protein synthesis shutdown and SG formation caused by eIF2α phosphorylation, and viruses can block the cell replication cycle through the PERK-eIF2α pathway, providing a favorable environment for their own replication. Subsequently, viruses can induce host cell autophagy or apoptosis through the eIF2α-ATF4-CHOP pathway. Conclusions This review summarizes the role of eIF2α in viral infection to provide a reference for studying the interactions between viruses and hosts.

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HIV-1 requires Staufen1 to dissociate stress granules and to produce infectious viral particles

Cited by 31 publications

References 42 publications

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

The Late Domain of Prototype Foamy Virus Gag Facilitates Autophagic Clearance of Stress Granules by Promoting Amphisome Formation

The role of host eIF2α in viral infection

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