Contribution of the human parainfluenza virus type 3 HN-receptor interaction to pathogenesis in vivo

The envelope of human parainfluenza virus type 3 (HPF3) contains two viral glycoproteins, the hemagglutinin-neuraminidase (HN) protein and the fusion (F) protein. In a previous study, highly fusogenic variant HPF3 viruses wer e isolated, including two, C-0 and C-22, that exhibit increased avidity for sialic acid receptors due to single amino acid changes in the HN protein a nd one, C-28, that has decreased neuraminidase activity relative to that of the wild type (wt) and is delayed in the release of virus particles into t he supernatant fluid. These variants form very large plaques and destroy a cell monolayer more rapidly than does wt HPF3 in cell culture. These varian t viruses allowed us to formulate hypotheses about the roles of HN in patho genesis. We investigated the behavior of wt HPF3 and the three variant viru ses in the cotton rat model. In the cotton rat, there was no delayed cleara nce of any of the variant viruses compared to that of the wt. The variant p laque morphology was preserved in vivo, and there was no reversion to the w t phenotype in the infected animals. In spite of a slight advantage of wt v irus in viral titer, there were no differences in the severities of peribro nchiolitis between wt viruses and the variants. However, there were marked differences in severities in alveolitis and interstitial pneumonitis when e ach of the three variants was compared to the wt, with the variants causing enhanced disease. Thus, despite similar or lower viral titers and similar clearance rates, the variants caused more extensive disease in the lung. Th e results show that mutations in HN conferring altered fusion properties in cell culture also confer striking differences in the ability of HPF3 to ca use extensive disease in the cotton rat lung and that this effect is dissoc iated from any effect on viral replication.