Human Immunodeficiency Virus (HIV), agent responsible for the AIDS pandemic, originated from interspecies transmissions of simian lentiviruses. Understanding the molecular interactions between HIV and the host cell is a major objective for advancing the fight against HIV/AIDS. In particular, the identification of new players in innate immunity to HIV not only contributes to our understanding of its adaptation to humans, but also provides broader information on the antiviral defense employed by the host. In this regard, the SAMD9 and SAMD9L genes appear as candidates of interest. Constituting a gene family involved in genetic auto-inflammatory diseases, SAMD9/9L are also described as antiviral against poxviruses. Furthermore, SAMD9L was identified in a screen as a potential HIV inhibitor. However, their role and implication regarding HIV remained unknown. This thesis work reveals that SAMD9 and SAMD9L have opposite effects on HIV replication, at the level of viral protein synthesis. While SAMD9 promotes HIV-1 replication, SAMD9L exerts a strainspecific antiviral action against HIV-1, HIV-2, and simian lentiviruses. In addition, we identified a nuclease site essential for the antiviral activity of SAMD9L against HIV. This active site is also decisive in inhibiting cell translation, in particular of deleterious SAMD9/9L variants implicated in severe genetic diseases. Furthermore, our evolutionary analyzes based on sequences and predicted structures show the presence of homologous proteins to SAMD9/9L in bacteria, which would also be involved in antiviral immunity. Despite a potential conservation over billions of years of evolution, these genes are rapidly evolving at the genomic and genetic levels, with typical traces of host-pathogen genetic conflicts within mammals. Thanks to complementary functional assays, we showed that some of these variations within great apes may be adaptations to lentiviruses. In conclusion, this project discovers and characterizes SAMD9 and SAMD9L as host factors modulating HIV replication and more broadly highlights their importance in living immunity.
Gratuit