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Internalization and intracellular retention of CD4 are two separate functions of the human immunodeficiency virus type 1 Nef protein

Nicoletta Casartelli^1,

¹ Division of Immunology and Infectious Disease, Children's Hospital Bambino Gesù, 00165 Rome, Italy
² Department of Experimental Medicine, ‘La Sapienza’ University of Rome, Italy

Correspondence
Margherita Doria
doria{at}uniroma2.it

The pathogenic Nef protein of the human immunodeficiency virus type 1 (HIV-1) downregulates CD4 by inducing its endocytosis and by inhibiting the transport of the receptor to the cell membrane. By means of in vivo-selected mutations, we show that L37, P78 and E177 residues of Nef are required for its effect on CD4 internalization and recycling but dispensable for Nef-induced retention and degradation of intracellular CD4. Of note, the function of Nef on the anterograde transport of newly synthesized CD4 molecules is irrelevant in cells with a slow constitutive CD4 turnover such as T cell lines. Moreover, we show that a mutated CD4 that is unresponsive to Nef-mediated endocytosis, CD4LL₁₄₄AA, is retained intracellularly and degraded by Nef like wild-type CD4. Thus, Nef's abilities to enhance endocytosis and induce intracellular retention of CD4 are mediated by separate protein surfaces and occur through distinct mechanisms.

Present address: Virus and Immunity Group, Department of Virology, Institut Pasteur, 75724 Paris Cedex 15, France.

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