Apr 23, 2020

Structural Basis of CD4 Downregulation by HIV-1 Nef

BioRxiv : the Preprint Server for Biology
Y. KwonXiaofei Jia


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.

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