Abstract
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 language | English (US) |
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Pages (from-to) | 121-133 |
Number of pages | 13 |
Journal | Cell Host and Microbe |
Volume | 1 |
Issue number | 2 |
DOIs | |
State | Published - Apr 19 2007 |
Keywords
- MICROBIO
- MOLIMMUNO
- SIGNALING
ASJC Scopus subject areas
- Parasitology
- Microbiology
- Virology