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Structure of HIV-2 Nef Reveals Unique Features Distinct from HIV-1 Involved in Immune Regulation

65 Pages Posted: 7 Oct 2019 Sneak Peek Status: Review Complete

See all articles by Kengo Hirao

Kengo Hirao

Hokkaido University - Faculty of Pharmaceutical Sciences

Sophie Andrews

University of Oxford - Nuffield Department of Medicine

Kimiko Kuroki

Hokkaido University - Faculty of Pharmaceutical Sciences

Hiroki Kusaka

Hokkaido University - Faculty of Pharmaceutical Sciences

Takashi Tadokoro

Hokkaido University - Faculty of Pharmaceutical Sciences

Shunsuke Kita

Hokkaido University - Faculty of Pharmaceutical Sciences

Toyoyuki Ose

Hokkaido University - Faculty of Pharmaceutical Sciences

Sarah Rowland-Jones

University of Oxford - Nuffield Department of Medicine

Katsumi Maenaka

Hokkaido University - Faculty of Pharmaceutical Sciences

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Abstract

The HIV accessory protein Nef plays a major role in establishing and maintaining infection, particularly through immune evasion. Many HIV-2 infected people experience long-term viral control and survival, resembling HIV-1 elite control. HIV-2 Nef has overlapping but also distinct functions from HIV-1 Nef. Here we report the crystal structure of HIV-2 Nef core. The dileucine sorting motif forms a helix bound to neighboring molecules, and moreover, isothermal titration calorimetry demonstrated that the CD3 endocytosis motif can directly bind to HIV-2 Nef, ensuring AP-2 mediated endocytosis for CD3. The highly-conserved C-terminal region forms a α-helix, absent from HIV-1. We further determined the structure of SIV Nef harboring this region, demonstrating similar C-terminal α-helix, which may contribute to AP-1 binding for MHC-I downregulation. These results provide new insights into the distinct pathogenesis of HIV-2 infection.

Keywords: HIV-2, Nef, x-ray crystallography, immune evasion, HIV, SIV, sorting motif, kinase

Suggested Citation

Hirao, Kengo and Andrews, Sophie and Kuroki, Kimiko and Kusaka, Hiroki and Tadokoro, Takashi and Kita, Shunsuke and Ose, Toyoyuki and Rowland-Jones, Sarah and Maenaka, Katsumi, Structure of HIV-2 Nef Reveals Unique Features Distinct from HIV-1 Involved in Immune Regulation (October 3, 2019). Available at SSRN: https://ssrn.com/abstract=3464031 or http://dx.doi.org/10.2139/ssrn.3464031
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Kengo Hirao

Hokkaido University - Faculty of Pharmaceutical Sciences ( email )

Japan

Sophie Andrews

University of Oxford - Nuffield Department of Medicine

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Kimiko Kuroki

Hokkaido University - Faculty of Pharmaceutical Sciences ( email )

Japan

Hiroki Kusaka

Hokkaido University - Faculty of Pharmaceutical Sciences ( email )

Japan

Takashi Tadokoro

Hokkaido University - Faculty of Pharmaceutical Sciences ( email )

Japan

Shunsuke Kita

Hokkaido University - Faculty of Pharmaceutical Sciences ( email )

Japan

Toyoyuki Ose

Hokkaido University - Faculty of Pharmaceutical Sciences ( email )

Japan

Sarah Rowland-Jones

University of Oxford - Nuffield Department of Medicine ( email )

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Katsumi Maenaka (Contact Author)

Hokkaido University - Faculty of Pharmaceutical Sciences ( email )

Japan

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