| May 05, 2017 HIV-1 competition experiments in humanized mice show that APOBEC3H imposes selective pressure and promotes virus adaptation |
Yusuke Nakano1, Naoko Misawa1, Guillermo Juarez-Fernandez1, Miyu Moriwaki1,2, Shinji Nakaoka3,4, Takaaki Funo5, Eri Yamada1, Andrew Soper1, Rokusuke Yoshikawa1,a, Diako Ebrahimi6,7,8,9, Yuuya Tachiki1,5,10, Shingo Iwami4,5,10, Reuben S Harris6,7,8,9,11, Yoshio Koyanagi1 and Kei Sato1,10*
1Laboratory of Systems Virology, Department of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University; 2Graduate School of Biostudies, Kyoto University; 3Institute of Industrial Sciences, The University of Tokyo; 4PRESTO, Japan Science and Technology Agency; 5Mathematical Biology Laboratory, Department of Biology, Faculty of Sciences, Kyushu University; 6Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota; 7Masonic Cancer Center, University of Minnesota; 8Institute for Molecular Virology, University of Minnesota; 9Center for Genome Engineering, University of Minnesota; 10CREST, Japan Science and Technology Agency; 11Howard Hughes Medical Institute, University of Minnesota
PLoS Pathog. 2017 May 5;13(5):e1006348. doi: 10.1371/journal.ppat.1006348.
Abstract
APOBEC3 family proteins are DNA cytosine deaminases recognized for contributing to HIV-1 restriction and mutation. Prior studies have demonstrated that APOBEC3D, APOBEC3F, and APOBEC3G enzymes elicit a robust anti-HIV-1 effect in cell cultures and in humanized mouse models. Human APOBEC3H is polymorphic and can be categorized into three phenotypes: stable, intermediate, and unstable. However, the anti-viral effect of endogenous APOBEC3H in vivo has yet to be examined. Here we utilize a hematopoietic stem cell-transplanted humanized mouse model and demonstrate that stable APOBEC3H robustly affects HIV-1 fitness in vivo. In contrast, the selection pressure mediated by intermediate APOBEC3H is relaxed. Intriguingly, viral genomic RNA sequencing reveled that HIV-1 frequently adapts to better counteract stable APOBEC3H during replication in humanized mice. Molecular phylogenetic analyses and mathematical modeling suggest that stable APOBEC3H may be a critical factor in human-to-human viral transmission. Taken together, this study provides evidence that stable variants of APOBEC3H impose selective pressure on HIV-1.
Figure:Dynamics of hyper/hypo HIV-1 dissemination in human population.
(A) A phylogenetic tree of Vif. The Vif sequences were extracted from HIV-1 sequence database and the phylogenetic tree was constructed. The branches of hyper Vif sequences are indicated with pink. Each color surrounding the phylogenetic tree represents viral subtype (A1-K). Scale bar indicates 5.0 amino acid substitutions per site. (B) The percentage of hyper Vif sequences in each subtype and group. (C) Phenotype of primary HIV-1 isolates against stable APOBEC3H. TF, transmitted/founder; CC, chronic control. (D) Distribution of hyper HIV-1 and individuals with stable A3H in the world. The percentages of hyper HIV-1 (pink, top) and stable A3H haplotype (green, bottom) in each region (Europe, Africa, Asia and North America; represented in bold) and country were obtained, and these two values are indicated by heatmap. The Vif amino acids at positions 39 and 48 are shown in logoplot, and the residues associated with hyper Vif are represented in pink. Note that the information of the proportion of A3H haplotype is not available in Russia, Australia, Central America and South America. (E) Mathematical modeling of the dissemination of hyper HIV-1 in human population. The prevalence of hyper HIV-1 in the human population with different stable A3H proportion was simulated by the mathematical model. The simulated prediction is shown with purple line. Red and Black dots indicate the results from respective regions and countries.