In enveloped viruses, post-translational proteolytic activation is a critical step for the fusion activity and thus for the infectivity of the virus. In addition to the membrane receptors for the viruses, proteolytic activation is indispensable for effective virus spread in the infected host and it is a prime determinant for pathogenicity. Here we described the host cellular processing
proteases,
tryptase Clara and
tryptase TL2, which proteolytically activate the infectivity of
influenza A and Sendai viruses in the respiratory tract and HIV-1 in human CD4+ T cells, respectively. A novel
trypsin-like
protease, designated
tryptase Clara, was purified from rat lung. The
enzyme is localized in Clara cells of the bronchial epithelium and is secreted into the airway lumen. The
enzyme specifically recognizes the consensus cleavage motif Gln(Glu)-X-Arg of
influenza A and Sendai viruses and proteolytically activates the envelope fusion
glycoproteins of the progeny viruses extracellularly in the airway lumen. Human
mucus protease inhibitor and
pulmonary surfactant in airway fluid inhibited the proteolytic activation of these viruses and also suppressed multiple cycles of viral replication in vitro. These results suggest that an imbalance between the amount of
tryptase Clara and that of endogenous inhibitors in airway fluid is a prime determinant for pneumopathogenicity of the viruses. Therefore supplementing an endogenous inhibitor at therapeutic doses may protect against
virus infection. In HIV-1
infection, binding of the gp120 envelope
glycoprotein to the
CD4 receptor is not sufficient in itself to allow virus entry, and an additional component(s) in the membrane is required for cell
infection as a cofactor. We isolated a
serine protease named
tryptase TL2, in the membrane of CD4+ lymphocytes, which specifically binds to the V3 loop of HIV-1 gp120 as a cofactor. After binding,
tryptase TL2 proteolytically processed gp120 into two
protein species of 70 and 50 kDa and the cleavage was suppressed by a
neutralizing antibody against the V3 loop. The
amino acids that constitute the cleavage sites in the V3 loop of almost all HIV isolates are variable, but they are restricted to those which are susceptible to chymotryptic and/or tryptic
enzyme. The multi-substrate specificity of
tryptase TL2, which has tryptic and chymotryptic specificities, may correspond tot he variability of the V3 loop. The selective cleavage of the V3 loop by
tryptase TL2 may lead to a conformational change of gp120, resulting in the dissociation of gp120 from gp41, exposing the fusogenic domain of the transmembrane
protein gp41 following virus-host cell fusion.