The conserved core of human immunodeficiency virus type 1 Nef is essential for association with Lck and for enhanced viral replication in T-lymphocytes.
The Nef protein of the primate lentiviruses, including human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV), is a myristylated protein associated with increased viral replication and enhanced pathogenicity. Both the potentiation of T-lymphocyte activation and the enhanced serine-phosphorylation of HIV-1 capsid by Nef correlate with increased viral replication. We report the functional interactions of the Nef proteins with Src kinases. The Nef proteins from HIV-1 and SIV bind to Lck as well as Hck, Lyn, and Fyn. The SH3 and SH2 domains of Lck are sufficient for coprecipitation with non-tyrosine-phosphorylated Nef proteins. The conserved core region of HIV-1 Nef is essential for the interaction with Lck and is also important for enhanced HIV-1 replication in T-lymphocytes. In addition, we show that SIV and HIV-1 Nef proteins are differentially tyrosine-phosphorylated. The kinase-active Lck tyrosine-phosphorylates SIVmac239 Nef but does not phosphorylate HIV-1 Nef. These data suggest that the association of Nef and Lck is central to the enhanced viral replication of HIV-1 and SIV in T-lymphocytes.
Cheng
H
H
Department of Microbiology and Pediatrics, New York University School of Medicine, New York, New York 10016, USA.
Hoxie
J P
JP
Parks
W P
WP
D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D015693:Gene Products, nef / Q000235:genetics / Q000378:metabolism; D015754:Genes, nef; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology* / Q000821:virology*; D014162:Transfection; D014779:Virus Replication / Q000235:genetics*; D054311:nef Gene Products, Human Immunodeficiency Virus; D019061:src-Family Kinases / Q000378:metabolism
D015693:Gene Products, nef; D011994:Recombinant Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases