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

• DOI: 10.1371/journal.pbio.3002696
• Publication Date: 2024-07-03T17:22:50Z
• Authors: Alexandre Legrand; Clara Dahoui; Clément De La Myr...; Kodie Noy; Laura Guiguettaz; Margaux Versapuech; Clara Loyer; Margaux Pillon; Mégane Wcislo; Laurent Guéguen; Clarisse Berlioz-...; Andrea Cimarelli; Mathieu Mateo; Francesca Fiorini; Emiliano P. Ricci; Lucie Etienne
• Keywords: QH301-705.5; Tumor Suppressor Proteins; Lentiviruses, Primate; Intracellular Signaling Peptides and Proteins; 610; HIV Infections; Virus Replication; [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity; Antiviral Restriction Factors; HEK293 Cells; [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases; Protein Biosynthesis; [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology; HIV-1; Humans; Animals; Biology (General); Research Article

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