HIV-1 Nef Targets MHC-I and CD4 for Degradation Via a Final Common β-COP–Dependent Pathway in T Cells

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Abstract
To facilitate viral infection and spread, HIV-1 Nef disrupts the surface expression of the viral receptor (CD4) and molecules capable of presenting HIV antigens to the immune system (MHC-I). To accomplish this, Nef binds to the cytoplasmic tails of both molecules and then, by mechanisms that are not well understood, disrupts the trafficking of each molecule in different ways. Specifically, Nef promotes CD4 internalization after it has been transported to the cell surface, whereas Nef uses the clathrin adaptor, AP-1, to disrupt normal transport of MHC-I from the TGN to the cell surface. Despite these differences in initial intracellular trafficking, we demonstrate that MHC-I and CD4 are ultimately found in the same Rab7+ vesicles and are both targeted for degradation via the activity of the Nef-interacting protein, β-COP. Moreover, we demonstrate that Nef contains two separable β-COP binding sites. One site, an arginine (RXR) motif in the N-terminal α helical domain of Nef, is necessary for maximal MHC-I degradation. The second site, composed of a di-acidic motif located in the C-terminal loop domain of Nef, is needed for efficient CD4 degradation. The requirement for redundant motifs with distinct roles supports a model in which Nef exists in multiple conformational states that allow access to different motifs, depending upon which cellular target is bound by Nef. HIV is unique among viral pathogens in its capacity to cause chronic and progressive disease in almost all infected people. To accomplish this, HIV must evade the host immune response, especially cytotoxic T lymphocytes (CTLs), which normally function to lyse virally infected cells. HIV encodes a factor, Nef, which protects HIV infected cells from lysis by anti-HIV CTLs. To prevent CTL lysis, Nef interferes with the expression of host MHC-I, which is needed for CTL recognition of infected targets. A clear understanding of how Nef works has been hampered by its many complex functions. In addition to MHC-I, Nef protein disrupts the expression of multiple other cellular targets using different mechanisms and it is unclear how one protein can accomplish all these tasks. Here, we provide evidence that Nef acts as a highly flexible adaptor protein that is capable of utilizing different protein binding domains depending on which cellular target it is bound to. For example, we present evidence that Nef binding to MHC-I creates novel motifs that result in the recruitment of AP-1 and subsequently β-COP. This series of events results in the mis-localization of MHC-I from the cell surface to cellular degradative compartments, where MHC-I is destroyed.

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