BIOCHEMICAL AND GENETIC DEFINITION OF THE CELLULAR PROTEASE REQUIRED FOR HIV-1 GP160 PROCESSING

The surface glycoproteins of enveloped viruses bind to target cell rec eptors and trigger membrane fusion for infection. The human immunodefi ciency virus 1 (HIV-1) envelope glycoproteins gp120 (CD4 binding prote in) and gp41 (transmembrane fusion protein) are initially synthesized as a gp160 precursor. The intracellular cleavage of gp160 by a host ce ll 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 processi ng, and cell-surface expression have been successfully reproduced in t he yeast Saccharomy cerevisiae. Genetic and biochemical approaches are used for defining that the unique cellular protease, Kex2p, is direct ly responsible for HIV-gp160 processing in yeast, in vivo and in vitro . The yeast system described in this report represents a powerful stra tegy for identifying, characterizing and inhibiting the host T-cell pr otease essential for HIV infectivity and AIDS.