期刊
CELL HOST & MICROBE
卷 23, 期 1, 页码 110-+出版社
CELL PRESS
DOI: 10.1016/j.chom.2017.12.009
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资金
- AMED J-PRIDE [17fm0208006h0001]
- JST CREST
- JSPS KAKENHI [C 15K07166, 16KT0111, 16H06429, 16K21723, 17H05813]
- Takeda Science Foundation
- Salt Science Research Foundation
- Smoking Research Foundation
- Chube Ito Foundation
- Fordays Self-Reliance Support in Japan
- Mishima Kaiun Memorial Foundation
- Tobemaki Foundation
- JSPS Core-to-Core program, A. Advanced Research Networks
- AMED Research on HIV/AIDS [16fk0410203h002]
- JST PRESTO
- German Research Foundation [1923]
- Junior Professorship Programme of the state of Baden-Wuerttemberg
- International Graduate School in Molecular Medicine Ulm
- ERC Advanced grant
- Grants-in-Aid for Scientific Research [17H05813, 26287025, 15K07166, 16K13777, 15KT0107, 16KT0111, 16H04845, 15KT0147] Funding Source: KAKEN
The HIV-1-encoded accessory protein Vpu exerts several immunomodulatory functions, including counteraction of the host restriction factor tetherin, downmodulation of CD4, and inhibition of NF-kB activity to facilitate HIV-1 infection. However, the relative contribution of individual Vpu functions to HIV-1 infection in vivo remained unclear. Here, we used a humanized mouse model and HIV-1 strains with selective mutations in vpu to demonstrate that the anti-tetherin activity of Vpu is a prerequisite for efficient viral spread during the early phase of infection. Mathematical modeling and gain-of-function mutations in SIVcpz, the simian precursor of pandemic HIV-1, corroborate this finding. Blockage of interferon signaling combined with transcriptome analyses revealed that basal tetherin levels are sufficient to control viral replication. These results establish tetherin as a key effector of the intrinsic immune defense against HIV-1, and they demonstrate that Vpu-mediated tetherin antagonism is critical for efficient viral spread during the initial phase of HIV-1 replication.
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