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.
Bibliographical noteFunding Information:
This study was supported in part by CREST, JST (to KS); a Health Labour Sciences Research Grant 26361601 from MHLW (to KS); the Takeda Science Foundation; a Sumitomo Foundation Research Grant (to KS); the Imai Memorial Trust (to KS); the Ichiro Kanehara Foundation (to KS); the Kanae Foundation (to KS); the Suzuken Memorial Foundation (to KS); the Uehara Memorial Foundation (to KS); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to KS); Grants-in-Aid for Scientific Research C 15K07166 from JSPS (to KS), Scientific Research B (Generative Research Fields) 16KT0111 from JSPS (to KS) and Scientific Research on Innovative Areas 17H05813 (to KS) and 24115008 (to YK) from MEXT; JSPS Research Fellowship PD 15J06242 (to RY); the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Dynamic Approaches to Living System) from AMED (to EY); the JSPS Core-to-Core program, A. Advanced Research Networks (to RSH and YK); Research on HIV/AIDS 16fk0410203h0002 from AMED (to YK); National Institute for Allergy and Infectious Disease R37-AI064046 (to RSH); and National Cancer Institute R21-CA206309 (to RSH). RSH is an Investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank Drs. Beatrice H. Hahn, Frederic Bibollet-Ruche, and Nicholas F. Parrish (University of Pennsylvania, USA) and Drs. Frank Kirchhoff and Daniel Sauter (Ulm University Medical Center, Germany) for providing materials, Dr. Osamu Ohara (RIKEN Yokohama Institute, Japan) for technical assistance of RNA-seq analyses, and Dr. Terumasa Ikeda (University of Minnesota, USA) for crucial suggestions, and Dr. Dong Sung An (University of California, Los Angeles, USA) for providing human CD34+hematopoietic stem cells. We also thank Ms. Kotubu Misawa for her dedicated support.
© 2017 Nakano et al.