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

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.

Duplication as a source of genetic innovation for «antiviral genes¼.

The antiviral proteins, also known as restriction factors, are the primary cellular defense against viral pathogens. These proteins from the innate immune system are in direct interactions with viral proteins. These antagonistic interactions come in two flavors: restriction factors are able to directly target the virus to restrict its replication and/or they may be the target of viral antagonists. Such long-term antagonistic virus-host interactions have set up an evolutionary "arms-race" between the two adversarial entities. This genetic conflict leads to a rapid evolution of viruses and antiviral genes. In particular, amino acids at the virus-host interface change more frequently than expected over time. On the other hand, more drastic host genome modifications have also been selected over time to counteract the rapid evolution of viruses. Reflecting the fact that numerous restriction factors belong to a gene family, it appears that duplication of antiviral genes has occurred frequently during the course of evolution. Here, we will review how duplication of antiviral genes has been selected in the host and how the divergence and plasticity of the duplicated genes may have been advantageous in the virus-host genetic conflict. We will also briefly expose the limits to such innate immune gene expansion.