# Coevolution of Lentiviral Vif with Host A3F and A3G: Insights from Computational Modelling and Ancestral Sequence Reconstruction

## TL;DR

This study explores how lentiviral Vif proteins and host A3F/A3G proteins coevolved using structural modeling and ancestral sequence reconstruction.

## Contribution

The study reveals structural and evolutionary patterns of A3F, A3G, and Vif across primates through 3D modeling and ancestral reconstruction.

## Key findings

- Inactive CD1 domains show higher sequence diversity and positive charges compared to active CD2 domains.
- A3F and A3G differ in loop 7’ interaction strategies, indicating distinct functional adaptations.
- Vif charge variation correlates with host species, reflecting coevolution with A3 proteins.

## Abstract

The evolutionary arms race between host restriction factors and viral antagonists provides crucial insights into immune system evolution and viral adaptation. This study investigates the structural and evolutionary dynamics of the double-domain restriction factors A3F and A3G and their viral inhibitor, Vif, across diverse primate species. By constructing 3D structural homology models and integrating ancestral sequence reconstruction (ASR), we identified patterns of sequence diversity, structural conservation, and functional adaptation. Inactive CD1 (Catalytic Domain 1) domains displayed greater sequence diversity and more positive surface charges than active CD2 domains, aiding nucleotide chain binding and intersegmental transfer. Despite variability, the CD2 DNA-binding grooves remained structurally consistent with conserved residues maintaining critical functions. A3F and A3G diverged in loop 7’ interaction strategies, utilising distinct molecular interactions to facilitate their roles. Vif exhibited charge variation linked to host species, reflecting its coevolution with A3 proteins. These findings illuminate how structural adaptations and charge dynamics enable both restriction factors and their viral antagonists to adapt to selective pressures. Our results emphasize the importance of studying structural evolution in host–virus interactions, with implications for understanding immune defense mechanisms, zoonotic risks, and viral evolution. This work establishes a foundation for further exploration of restriction factor diversity and coevolution across species.