Deletion of N-terminal myristoylation site of HIV Nef abrogates both MHC-1and CD4 down-regulation

HIV-1 Nef is a desirable vaccine component because it is expressed early an d abundantly during HIV infection, and contains many CTL, T-helper cell, an d B-cell epitopes. Nef, however, down-regulates MHC-1 and CD4 cell surface expression, contributing to viral escape from host immunity. To prevent Nef from down-regulating both MHC-1 and CD4 while preserving most CTL epitopes , a panel of Nef mutants was constructed and assessed. Some mutants, as exp ected, modulated either MHC-1 or CD4 expression, Others prevented down-regu lation of both proteins but sacrificed numerous immunogenic epitopes. Delet ion of 19 N-terminal amino acids including the myristoylation signal from N ef completely abrogated both MHC-1 and CD4 down-regulation while preserving most CTL, T-helper and B-cell epitopes. Our results demonstrate that the m yristoylation signal in the Nef protein is critical for Nef-mediated endocy tosis of both MHC-1 and CD4. Non-myristoylated Nef containing a full comple ment of CTL epitopes has greater potential as a vaccine component than wild -type Nef. (C) 2001 Elsevier Science B.V. All rights reserved.