Maturation of HIV envelope glycoprotein precursors by cellular endoproteases

The entry of enveloped Viruses into its host cells is a crucial step for th e propagation of viral infection. The envelope glycoprotein complex control s viral tropism and promotes the membrane fusion process. The surface glyco proteins of enveloped viruses are synthesized as inactive precursors and so rted through the constitutive secretory pathway of the infected cells. To b e infectious, most of the viruses require viral envelope glycoprotein matur ation by host cell endoproteases. In spite of the strong variability of pri mary sequences observed within different viral envelope glycoproteins, the endoproteolytical cleavage occurs mainly in a highly conserved domain at th e carboxy terminus of the basic consensus sequence (Arg-X-Lys/ Arg-Arg down arrow). The same consensus sequence is recognized by the kexin/subtilisin- like serine proteinases (so called convertases) in many cellular substrates such as prohormones, proprotein of receptors, plasma proteins, growth fact ors and bacterial toxins. Therefore, several groups of investigators have e valuated the implication of convertases in viral envelope glycoprotein clea vage. Using the vaccinia virus overexpression system, furin was first shown to mediate the proteolytic maturation of both human immunodeficiency virus (HIV-1) and influenza Virus envelope glycoproteins. In vitro studies demon strated that purified convertases directly and specifically cleave viral en velope glycoproteins. Although these studies suggested the participation of several enzymes belonging to the convertases family, recent data suggest t hat other protease families may also participate in the HIV envelope glycop rotein processing. Their role in the physiological maturation process is st ill hypothetical and the molecular mechanism of the cleavage is not well do cumented. Crystallization of the hemagglutinin precursor (HA0) of influenza virus allowed further understanding of the molecular interaction between v iral precursors and the cellular endoproteases. Furthermore, relationships between differential pathogenicity of influenza strains and their susceptib ility to cleavage are molecularly funded. Here we review the most recent da ta and recent insights demonstrating the crucial role played by this activa tion step in virus infectivity. We discuss the cellular endoproteases that are implicated in HIV gp160 endoproteolytical maturation into gp120 and gp4 1. (C) 2000 Elsevier Science B.V. All rights reserved.