HIV-1 competition experiments in humanized mice show that APOBEC3H imposes selective pressure and promotes virus adaptation

Apobec3 (a3) family proteins are dna cytosine deaminases recognized for contributing to hiv-1 restriction and mutation. prior studies have demonstrated that a3d,a3f,and a3g enzymes elicit a robust anti-hiv-1 effect in cell cultures and in humanized mouse models. human a3h is polymorphic and can be categorized into three phenotypes: stable,intermediate,and unstable. however,the anti-viral effect of endogenous a3h in vivo has yet to be examined. here we utilize a hematopoietic stem cell-transplanted humanized mouse model and demonstrate that stable a3h robustly affects hiv-1 fitness in vivo. in contrast,the selection pressure mediated by intermediate a3h is relaxed. intriguingly,viral genomic rna sequencing reveled that hiv-1 frequently adapts to better counteract stable a3h during replication in humanized mice. molecular phylogenetic analyses and mathematical modeling suggest that stable a3h may be a critical factor in human-to-human viral transmission. taken together,this study provides evidence that stable variants of a3h impose selective pressure on hiv-1. © 2017 nakano et al.