HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 NEF AND P56(LCK) PROTEIN-TYROSINE KINASE INTERACT WITH A COMMON ELEMENT IN CD4 CYTOPLASMIC TAIL

The human immunodeficiency virus type 1 nef gene induces endocytosis of CD4 antigen and disrupts the association between CD4 and p56(lck) protein-tyrosine kinase (EC 2.7.1.112). We demonstrate that in T cells these effects of the viral protein require a cluster of hydrophobic amino acids in a membrane proximal region of the CD4 cytoplasmic tail; other amino acids in the C-terminal segment of CD4 cytoplasmic tail also contribute to the interaction. Mutations in CD4 that prevent down-modulation by Nef also decrease CD4 association with p56(lck) and prevent Nef-induced disruption of CD4-p56(lck) complexes. Together, the overlap in CD4 sequences required for interaction with Nef and p56(lck) and the tight correlation between Nef-induced CD4 down-modulation and disruption of CD4-p56(lck) association suggest that Kef, or cellular factors recruited by Nef, interact with this segment of CD4 to displace p56(lck) from the complex and induce CD4 endocytosis.