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Structural Basis of CD4 Downregulation by HIV-1 Nef

By Yonghwa Kwon, Robyn Kaake, Ignacia Echeverria, Marissa Suarez, Charlotte Stoneham, Peter W. Ramirez, Jacob Kress, Rajendra Singh, Andrej Sali, Nevan Krogan, John Guatelli, Xiaofei Jia

Posted 23 Apr 2020
bioRxiv DOI: 10.1101/2020.04.21.054007

The HIV-1 Nef protein suppresses multiple immune surveillance mechanisms to promote viral pathogenesis and is an attractive target for the development of novel therapeutics. A key function of Nef is to remove the CD4 receptor from the cell surface by hijacking clathrin- and AP2-dependent endocytosis. However, exactly how Nef does this has been elusive. Here, we present a high-resolution crystal structure that describes the underlying mechanism. An intricate combination of conformational changes occurs in both Nef and AP2 to enable CD4 binding and downregulation. Strikingly, a pocket on Nef previously identified as crucial for recruiting class I MHC is also responsible for recruiting CD4, revealing a potential approach to inhibit two activities of Nef and sensitize the virus to immune clearance. ### Competing Interest Statement The authors have declared no competing interest.

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