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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...

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Detalles Bibliográficos
Autores principales: Nakano, Yusuke, Misawa, Naoko, Juarez-Fernandez, Guillermo, Moriwaki, Miyu, Nakaoka, Shinji, Funo, Takaaki, Yamada, Eri, Soper, Andrew, Yoshikawa, Rokusuke, Ebrahimi, Diako, Tachiki, Yuuya, Iwami, Shingo, Harris, Reuben S., Koyanagi, Yoshio, Sato, Kei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435363/
https://www.ncbi.nlm.nih.gov/pubmed/28475648
http://dx.doi.org/10.1371/journal.ppat.1006348
Descripción
Sumario: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.