Down-regulation of CD4 molecules by the expression of Nef: a quantitative analysis of CD4 antigens on the cell surfaces.

Nef is one of the non-structural genes encoded by human immunodeficiency viruses. The protein product is associated with the cellular and plasma membranes, and is synthesized soon after entry of the virus. However, little is known about its functions relevant to viral replication and cytopathogenesis. CD4 is considered to be a crucial molecule for the signal transduction and maturation of T cells, and also serves as the receptor for HIV-1. It has been suggested that the down-regulation of cell surface CD4 by Nef proteins is somehow controversial. In order to evaluate the effects of Nef on the CD4 molecule, we constructed a CD4+ monocytoid cell line in which the HIV-1 nef gene was placed under the transcriptional control of the human metallothionein IIA promoter. The analysis of this cellular clone showed that CD4 on the cell surface was down-regulated when Nef proteins were induced. The amount of CD4 antigens on the cell surface correlated inversely with the level of Nef protein expression. This down-regulation of CD4 antigens by Nef was found to occur at the post-translational level. These results showed that the nef gene could modulate the pathophysiology of AIDS by altering the surface CD4 expression.