Human Immunodeficiency Virus Nef Induces Rapid Internalization of the T-Cell Coreceptor CD8αβ

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Abstract
Human immunodeficiency virus (HIV) Nef is a membrane-associated protein decreasing surface expression of CD4, CD28, and major histocompatibility complex class I on infected cells. We report that Nef strongly down-modulates surface expression of the β-chain of the CD8αβ receptor by accelerated endocytosis, while CD8 α-chain expression is less affected. By mutational analysis of the cytoplasmic tail of the CD8 β-chain, an FMK amino acid motif was shown to be critical for Nef-induced endocytosis. Although independent of CD4, endocytosis of the CD8 β-chain was abrogated by the same mutations in Nef that affect CD4 down-regulation, suggesting common molecular interactions. The ability to down-regulate the human CD8 β-chain was conserved in HIV-1, HIV-2, and simian immunodeficiency virus SIVmac239 Nef and required an intact AP-2 complex. The Nef-mediated internalization of receptors, such as CD4, major histocompatibility complex class I, CD28, and CD8αβ, may contribute to the subversion of the host immune system and progression towards AIDS.