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Mechanisms of CD4 Downregulation by the Nef and Vpu Proteins of Primate Immunodeficiency Viruses

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Human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), and simian immunodeficiency virus (SIV) are the etiological agents of acquired immunodeficiency syndrome (AIDS) in humans and a related disease in non-human primates. These viruses infect T cells and macrophages that express the surface glycoprotein, CD4, because this glycoprotein acts as a coreceptor for incoming virus particles. Once infection has occurred, however, the presence of CD4 poses problems for the virus life cycle, including the possibility of superinfection, premature binding of CD4 to nascent virus particles, and inhibition of virus release. Accordingly, primate immunodeficiency viruses have evolved at least two distinct mechanisms, mediated by the Nef and Vpu viral proteins, to “downregulate” CD4 in the host cells. Nef and Vpu are mainly expressed early and late, respectively, in the viral life cycle, ensuring continuous removal of CD4. Nef links mature CD4 to components of clathrin-dependent trafficking pathways at the plasma membrane, and perhaps in intracellular compartments, leading to internalization and delivery of CD4 to lysosomes for degradation. Vpu, on the other hand, interacts with newly-synthesized CD4 in the endoplasmic reticulum, linking CD4 to the SCF ubiquitin ligase and facilitating the entry of CD4 into the endoplasmic-reticulum-associated degradation pathway. These two mechanisms lead to a dramatic reduction of CD4 expression in infected cells and are essential for efficient virus replication and disease progression.

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Keywords: AIDS; CD4; ERAD; HIV; Nef; Vpu; clathrin; β-TrCP

Document Type: Research Article

Affiliations: Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Building 18T/Room 101, National Institutes of Health,Bethesda, MD 20892, USA.

Publication date: March 1, 2007

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  • Current Molecular Medicine is an interdisciplinary journal focused on providing the readership with current and comprehensive reviews on fundamental molecular mechanisms of disease pathogenesis, the development of molecular-diagnosis and/or novel approaches to rational treatment. The reviews should be of significant interest to basic researchers and clinical investigators in molecular medicine. Periodically the journal will invite guest editors to devote an issue on a basic research area that shows promise to advance our understanding of the molecular mechanism(s) of a disease or has potential for clinical applications.
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