The downregulation of CD4 and MHC-I by primate lentiviruses: a paradigm for the modulation of cell surface receptors.
The human and simian immunodeficiency viruses (HIV and SIV) downregulate the cell surface expression of CD4, their primary receptor, and of class I histocompatibility complex (MHC-I), a critical mediator of immune recognition. While the first of these effects seems important to preserve viral infectivity, the second likely promotes immune evasion. Three HIV-1 proteins, Nef, Env and Vpu, contribute to downregulate CD4, Env forms a complex with CD4 in the endoplasmic reticulum, thereby retaining the receptor in this compartment. Nef and Vpu, on the other hand, act as connectors between CD4 and specific intracellular trafficking pathways, targeting the receptor for degradation in the lysosome and the proteasome, respectively. Some of the downstream partners of the viral proteins in these events have been identified, and include the adaptor complex of clathrin-coated pits, the beta subunit of COP-I coatomer, and the ubiquitin pathway-related h-beta TrCP protein. HIV-induced MHC-I downregulation, mostly the effect of Nef, also reflects a redistribution of this receptor, with its accumulation in the Golgi. The modalities of this process, however, are as yet imperfectly understood. New evidence indicates that the mechanisms employed by primate lentiviruses to downmodulate CD4 and MHC-I are also exploited by a number of cellular regulatory processes.
Department of Genetics and Microbiology, University of Geneva, Switzerland.
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Piguet
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Schwartz
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Le Gall
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Trono
D033965:Adaptor Protein Complex alpha Subunits; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D015536:Down-Regulation; D015693:Gene Products, nef / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D016086:Lentivirus / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D011323:Primates; D011991:Receptors, Virus / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus; D000086082:Viroporin Proteins
D033965:Adaptor Protein Complex alpha Subunits; D033942:Adaptor Proteins, Vesicular Transport; D015704:CD4 Antigens; D015693:Gene Products, nef; D015395:Histocompatibility Antigens Class I; D054298:Human Immunodeficiency Virus Proteins; D008565:Membrane Proteins; D011991:Receptors, Virus; D014759:Viral Envelope Proteins; D054334:Viral Regulatory and Accessory Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins