Biochemical and genetic definition of the cellular protease required for HIV-1 gp160 processing.

The surface glycoproteins of enveloped viruses bind to target cell receptors and trigger membrane fusion for infection. The human immunodeficiency virus 1 (HIV-1) envelope glycoprotein gp120 (CD4 binding protein) and gp41 (transmembrane fusion protein) are initially synthesized as a gp160 precursor. The intracellular cleavage of gp160 by a host cell protease during transit through the secretory pathway is essential for viral activities such as infectivity, membrane fusion, and T-cell syncytium formation. We report that gp160 biogenesis, protein processing, and cell-surface expression have been successfully reproduced in the yeast Saccharomyces cerevisiae. Genetic and biochemical approaches are used for defining that the unique cellular protease, Kex2p, is directly responsible for HIV-gp160 processing in yeast, in vivo and in vitro. The yeast system described in this report represents a powerful strategy for identifying, characterizing and inhibiting the host T-cell protease essential for HIV infectivity and AIDS.