Structural Basis of APOBEC Functions and HIV Restriction

APOBEC proteins, a diverse family of cytosine deaminases, are pivotal to multiple biological processes, ranging from innate and acquired immunity to cholesterol metabolism and oncogenesis. Central to their function is the ability to edit nucleic acids, a mechanism exploited to restrict viral infections, including those caused by retroviruses like HIV and certain DNA viruses. In addition, APOBECs serve as guardians against endogenous retroelements that could compromise genomic integrity. However, when their regulation falters, these enzymes can become deleterious, contributing to immune deficiencies such as hyper-IGM syndrome, genomic instability, and even cancer. In primates, the APOBEC3 (A3) subfamily consists of seven members (A3A-H), each exhibiting distinct antiviral activities. Some of these, notably the double-domain A3s, thwart HIV/SIV by deaminating viral cDNA or inhibiting its transcription through deaminase-independent pathways. Yet, the battle is not one-sided: HIV and SIV viruses counteract by deploying the Viral Infectivity Factor (Vif), which co-opts host cellular machinery to degrade A3 proteins, thus neutralizing their antiviral arsenal. Our proposal aims to dissect the intricate structural dynamics that underpin APOBEC function and regulation, particularly how these proteins engage with nucleic acids and how HIV evades their defenses. By elucidating the molecular choreography between A3s and the diverse Vif proteins of HIV/SIV, we seek not only to advance our understanding of viral pathogenesis but also to open avenues for innovative therapeutic interventions against HIV/AIDS and APOBEC- related cancers. The specific goals of this project are to characterize the interactions of nucleic acids with double-domain A3s, to unravel the mechanisms of HIV restriction by these proteins, and to understand the molecular strategies employed by Vif proteins to disable various A3s. Through these studies, we hope to uncover fundamental principles that govern APOBEC functions and their role in immune defense.