The pathogenicity of human immunodeficiency virus (HIV) type 1 Nef in CD4C/HIV transgenic mice is abolished by mutation of its SH3-binding domain, and disease development is delayed in the absence of Hck

The human immunodeficiency virus type 1 (HIV-1) Nef protein is an important determinant of AIDS pathogenesis. We have previously reported that HIV-1 N ef is responsible for the induction of a severe AIDS-like disease in CD4C/H IV transgenic (Tg) mice. To understand the molecular mechanisms of this Nef -induced disease, we generated Tg mice expressing a mutated Nef protein in which the SH3 ligand-binding domain (P72XXP75XXP78) was mutated to A(72)XXA (75)XXQ(78). This mutation completely abolished the pathogenic potential of Net, although a partial downregulation of the CD4 cell surface expression was still observed in these Tg mice. We also studied whether Hck, one of th e effectors previously found to bind to this PXXP motif of Nef, was involve d in disease development. Breeding of Tg mice expressing wild-type Nef on a n hck(-/-) (knockout) background did not abolish any of the pathological ph enotypes. However, the latency of disease development was prolonged. These data indicate that an intact PXXP domain is essential for inducing an AIDS- like disease in CD4C/HIV Tg mice and suggest that interaction of a cellular effector(s) with this domain is required for the induction of this multior gan disease. Our findings indicate that Hck is an important, but not an ess ential, effector of Nef and suggest that another factor(s), yet to be ident ified, may be more critical for disease development.