Human-Specific Adaptations in Vpu Conferring Anti-tetherin Activity Are Critical for Efficient Early HIV-1 Replication In Vivo

Eri Yamada, Shinji Nakaoka, Lukas Klein, Elisabeth Reith, Simon Langer, Kristina Hopfensperger, Shingo Iwami, Gideon Schreiber, Frank Kirchhoff, Yoshio Koyanagi, Daniel Sauter, Kei Sato

Research output: Contribution to journalArticle

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Abstract

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-κB 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. The HIV-1-encoded accessory protein Vpu exerts several functions. Using a humanized mouse model and HIV-1 Vpu mutant viruses, Yamada et al. demonstrate that Vpu-mediated antagonism of the interferon-induced antiviral protein tetherin is critical for efficient viral spread during the initial phase of HIV-1 replication in vivo.

Original languageEnglish
Pages (from-to)110-120.e7
JournalCell Host and Microbe
Volume23
Issue number1
DOIs
Publication statusPublished - Jan 10 2018

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HIV-1
Interferons
HIV Infections
Mutation
Proteins
Gene Expression Profiling
Pandemics
Antiviral Agents
Viruses
Infection

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Virology

Cite this

Human-Specific Adaptations in Vpu Conferring Anti-tetherin Activity Are Critical for Efficient Early HIV-1 Replication In Vivo. / Yamada, Eri; Nakaoka, Shinji; Klein, Lukas; Reith, Elisabeth; Langer, Simon; Hopfensperger, Kristina; Iwami, Shingo; Schreiber, Gideon; Kirchhoff, Frank; Koyanagi, Yoshio; Sauter, Daniel; Sato, Kei.

In: Cell Host and Microbe, Vol. 23, No. 1, 10.01.2018, p. 110-120.e7.

Research output: Contribution to journalArticle

Yamada, E, Nakaoka, S, Klein, L, Reith, E, Langer, S, Hopfensperger, K, Iwami, S, Schreiber, G, Kirchhoff, F, Koyanagi, Y, Sauter, D & Sato, K 2018, 'Human-Specific Adaptations in Vpu Conferring Anti-tetherin Activity Are Critical for Efficient Early HIV-1 Replication In Vivo', Cell Host and Microbe, vol. 23, no. 1, pp. 110-120.e7. https://doi.org/10.1016/j.chom.2017.12.009
Yamada, Eri ; Nakaoka, Shinji ; Klein, Lukas ; Reith, Elisabeth ; Langer, Simon ; Hopfensperger, Kristina ; Iwami, Shingo ; Schreiber, Gideon ; Kirchhoff, Frank ; Koyanagi, Yoshio ; Sauter, Daniel ; Sato, Kei. / Human-Specific Adaptations in Vpu Conferring Anti-tetherin Activity Are Critical for Efficient Early HIV-1 Replication In Vivo. In: Cell Host and Microbe. 2018 ; Vol. 23, No. 1. pp. 110-120.e7.
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