HIV-1 Nef Assembles a Src Family Kinase-ZAP-70/Syk-PI3K Cascade to Downregulate Cell-Surface MHC-I

Chien Hui Hung, Laurel Thomas, Carl E. Ruby, Katelyn M. Atkins, Nicholas P. Morris, Zachary A. Knight, Isabel Scholz, Eric Barklis, Andrew D. Weinberg, Kevan M. Shokat, Gary Thomas

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


HIV-1 Nef, which is required for the efficient onset of AIDS, enhances viral replication and infectivity by exerting multiple effects on infected cells. Nef downregulates cell-surface MHC-I molecules by an uncharacterized PI3K pathway requiring the actions of two Nef motifs-EEEE65 and PXXP75. We report that the Nef EEEE65 targeting motif enables Nef PXXP75 to bind and activate a trans-Golgi network-localized Src family tyrosine kinase (SFK). The Nef/SFK complex then recruits and phosphorylates the tyrosine kinase ZAP-70, which binds class I PI3K to trigger MHC-I downregulation in primary CD4+ T cells. In promonocytic cells, Nef/SFK recruits the ZAP-70 homolog Syk to downregulate MHC-I, implicating this PI3K pathway in multiple HIV-1 reservoirs. Isoform-specific PI3K inhibitors repress MHC-I downregulation, identifying them as potential therapeutic agents to combat HIV-1. The discovery of this Nef-SFK-ZAP-70/Syk-PI3K signaling pathway explains the hierarchal role of the Nef motifs in effecting immunoevasion.

Original languageEnglish (US)
Pages (from-to)121-133
Number of pages13
JournalCell Host and Microbe
Issue number2
StatePublished - Apr 19 2007



ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology


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