SAMD9L acts as an antiviral factor against HIV-1 and primate lentiviruses by restricting viral and cellular translation - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue PLoS Biology Année : 2024

SAMD9L acts as an antiviral factor against HIV-1 and primate lentiviruses by restricting viral and cellular translation

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Sterile alpha motif domain-containing proteins 9 and 9-like (SAMD9/9L) are associated with life-threatening genetic diseases in humans and are restriction factors of poxviruses. Yet, their cellular function and the extent of their antiviral role are poorly known. Here, we found that interferon-stimulated human SAMD9L restricts HIV-1 in the late phases of replication, at the posttranscriptional and prematuration steps, impacting viral translation and, possibly, endosomal trafficking. Surprisingly, the paralog SAMD9 exerted an opposite effect, enhancing HIV-1. More broadly, we showed that SAMD9L restricts primate lentiviruses, but not a gammaretrovirus (MLV), nor 2 RNA viruses (arenavirus MOPV and rhabdovirus VSV). Using structural modeling and mutagenesis of SAMD9L, we identified a conserved Schlafen-like active site necessary for HIV-1 restriction by human and a rodent SAMD9L. By testing a gain-of-function constitutively active variant from patients with SAMD9L-associated autoinflammatory disease, we determined that SAMD9L pathogenic functions also depend on the Schlafen-like active site. Finally, we found that the constitutively active SAMD9L strongly inhibited HIV, MLV, and, to a lesser extent, MOPV. This suggests that the virus-specific effect of SAMD9L may involve its differential activation/sensing and the virus ability to evade from SAMD9L restriction. Overall, our study identifies SAMD9L as an HIV-1 antiviral factor from the cell autonomous immunity and deciphers host determinants underlying the translational repression. This provides novel links and therapeutic avenues against viral infections and genetic diseases.
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hal-04635756 , version 1 (04-07-2024)

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Alexandre Legrand, Clara Dahoui, Clément de la Myre Mory, Kodie Noy, Laura Guiguettaz, et al.. SAMD9L acts as an antiviral factor against HIV-1 and primate lentiviruses by restricting viral and cellular translation. PLoS Biology, 2024, 22 (7), pp.e3002696. ⟨10.1371/journal.pbio.3002696⟩. ⟨hal-04635756⟩
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