Structural and evolutionary analyses of host antiviral restriction factors

Abstract

Antiviral restriction factors are critical components of the host innate immune system. This thesis investigates the structural and evolutionary dynamics of two pivotal antiviral protein families: the Mx proteins and APOBEC3 (A3) proteins. The first section focuses on Mx proteins, which belong to the Dynamin superfamily of proteins (DSP). Comprehensive phylogenomic analyses demonstrate that Mx proteins predate the interferon signaling system in vertebrates. We elucidate the ancient monophyletic lineage of Mx proteins across diverse eukaryotes, revealing previously undescribed fungal and plant Mxorthologs. The evolutionary trajectory suggests recurrent viral appropriation of host DSPs, underscoring an ancient co evolutionary history of viral and antiviral functions within eukaryotes. The second section examines the structural basis of HIV-1 Vif antagonism of human A3G, a restriction factor that induces hypermutation in viral genomes. Using cryogenic electron microscopy, we resolved the structure of A3G bound to HIV-1 Vif and hijacked cellular proteins, highlighting RNA's role as a molecular glue facilitating the Vif-A3G interaction. This interaction underpins A3G antagonism, offering insights into the molecular arms race driving host-virus coevolution. Additionally, deep mutational scanning (DMS) of Vif proteins reveals evolutionary constraints and adaptive potential, enhancing our understanding of HIV-1 adaptation to host immune defenses. This thesis provides a comprehensive structural and evolutionary framework for understanding how host antiviral proteins and viral antagonists co-evolve, contributing to our broader knowledge of host-virus interactions.