CHAPTER 8 - The Role of the APOBEC3 Family of Cytidine Deaminases in Innate Immunity, G-to-A Hypermutation, and Evolution of Retroviruses

Abstract

The APOBEC3 family of cytidine deaminases comprises a novel group of innate immunity factors that counteract both exogenous and endogenous retroviruses. Initially identified as critical targets of the HIV-1 protein Vif, APOBEC3G (A3G) and APOBEC3F (A3F) are encapsidated into budding virions, where these proteins attack sequential steps of the reverse transcription process in the target cell by virtue of its ability to: (1) bind RNA and (2) catalyze G-to-A hypermutation in nascent single-stranded DNA. In resting CD4 T cells and monocytes, A3G in a low-molecular-mass (LMM) form also acts as a potent post-entry barrier against incoming HIV-1. However, T cell activation and differentiation of monocytes into macrophages recruits A3G into enzymatically inactive high-molecular-mass (HMM) complexes, thereby forfeiting its post-entry antiviral activity against HIV-1. Augmenting the antiviral properties of A3G, either by blocking the Vif–A3G interaction or carefully disrupting HMM complex formation, serve as potentially novel therapeutic approaches against HIV-1. Intriguingly, these same antiviral properties of A3G, as well as other APOBEC3 family members, may significantly contribute to the G-to-A mutational bias in retroviral genomes, raising the intriguing possibility that these innate factors may help directly shape the evolutionary diversity of retroviruses.