APOBEC3D and APOBEC3F Potently Promote HIV-1 Diversification and Evolution in Humanized Mouse Model

Kei Sato, Junko S. Takeuchi, Naoko Misawa, Taisuke Izumi, Tomoko Kobayashi, Yuichi Kimura, Shingo Iwami, Akifumi Takaori-Kondo, Wei Shau Hu, Kazuyuki Aihara, Mamoru Ito, Dong Sung An, Vinay K. Pathak, Yoshio Koyanagi

研究成果: Contribution to journalArticle査読

61 被引用数 (Scopus)

抄録

Several APOBEC3 proteins, particularly APOBEC3D, APOBEC3F, and APOBEC3G, induce G-to-A hypermutations in HIV-1 genome, and abrogate viral replication in experimental systems, but their relative contributions to controlling viral replication and viral genetic variation in vivo have not been elucidated. On the other hand, an HIV-1-encoded protein, Vif, can degrade these APOBEC3 proteins via a ubiquitin/proteasome pathway. Although APOBEC3 proteins have been widely considered as potent restriction factors against HIV-1, it remains unclear which endogenous APOBEC3 protein(s) affect HIV-1 propagation in vivo. Here we use a humanized mouse model and HIV-1 with mutations in Vif motifs that are responsible for specific APOBEC3 interactions, DRMR/AAAA (4A) or YRHHY/AAAAA (5A), and demonstrate that endogenous APOBEC3D/F and APOBEC3G exert strong anti-HIV-1 activity in vivo. We also show that the growth kinetics of 4A HIV-1 negatively correlated with the expression level of APOBEC3F. Moreover, single genome sequencing analyses of viral RNA in plasma of infected mice reveal that 4A HIV-1 is specifically and significantly diversified. Furthermore, a mutated virus that is capable of using both CCR5 and CXCR4 as entry coreceptor is specifically detected in 4A HIV-1-infected mice. Taken together, our results demonstrate that APOBEC3D/F and APOBEC3G fundamentally work as restriction factors against HIV-1 in vivo, but at the same time, that APOBEC3D and APOBEC3F are capable of promoting viral diversification and evolution in vivo.

本文言語英語
ジャーナルPLoS pathogens
10
10
DOI
出版ステータス出版済み - 10 1 2014

All Science Journal Classification (ASJC) codes

  • 寄生虫科
  • 微生物学
  • 免疫学
  • 分子生物学
  • 遺伝学
  • ウイルス学

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