8th International AIDS Conference Amsterdam, Netherlands — July 19-24, 1992

Int Conf AIDS 1992 Jul 19-24; 8:We46 (abstract no. WeA 1008)
Willey R, Maldarelli F, Chen MY, Martin MA, Strebel K; Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD 20892.

OBJECTIVES: Analysis of the HIV-1 vpu gene product and its effects on viral and cellular proteins.

METHODS: HIV-1 subgenomic and CD4 expression plasmids were generated using standard molecular biological techniques. Assays were performed by transfecting HeLa cells followed by metabolic labelling of transiently expressed proteins and subsequent identification by immunoprecipitation with specific antisera.

RESULTS: CD4 is a integral membrane glycoprotein that is synthesized at the endoplasmic reticulum (ER) and subsequently transported to the cell surface via the golgi system. HIV-infection of CD4+ cells leads to downmodulation of cell surface CD4 due at least in part to the formation of stable intracellular complexes between CD4 and the HIV-1 Env precursor polyprotein, gp160. This process "traps" both proteins in the ER and results in reduced surface expression of CD4 and gp120/gp41. We have recently demonstrated that the presence of the 81 amino acid integral membrane protein, Vpu, can reduce the formation of CD4/Env complexes resulting in increased gp160 processing and decreased CD4 stability. We have studied the effect of Vpu on CD4 stability and found that Vpu induces rapid degradation of CD4 reducing the half-life of CD4 from 6 hours to 12 minutes. By using defined gp160 and CD4 mutants it can be shown that this Vpu-induced degradation requires retention of CD4 in the ER which is facilitated through its binding to gp160.

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