MEASLES VIRUS - PERSISTENT VIRAL INFECTIONS, ANTIGENIC VARIATION AND HUMAN DISEASE

Abstract

Measles virus has been implicated in several chronic neurologic diseases of humans, i.e., subacute sclerosing panencephalitis (SSPE) and multiple sclerosis (MS). These diseases are thought to result from a persistent measles virus infection, most likely from viral mutants. Thus, it became important to determine how mutants of measles arise and to analyze their role in persistent viral infections and the pathogenisis of certain human diseases.;The results are basically in three parts. The first part shows that a wide range of genetically heterogeneous mutants arose early in the establishment of the persistent state, suggesting that these mutants play a major role in the early events of this infection. Experiments reported here found that interferon seemed to have a modulating effect on this infection. It is proposed that one function of the temperature-sensitive mutants produced in this infection is to induce interferon which in turn would inhibit the wild type virus present in the culture.;The second part concerns the search for anitgenic mutants of measles virus. To do this, monoclonal antibodies specific for measles virus proteins were obtained. Using monoclonal antibodies, a wide range of antigenic variation was evident (by neutralization differences) among several SSPE and wild type measles viruses. By using neutralizing monoclonal antibodies, stable antigenic (nonneutralized) variants of measles virus were isolated at different antigenic sites. Peptide analysis of the hemagglutinin protein of one of these variants confirmed a single or limited number of amino acid changes in this protein, consistent with a spontaneously arising mutant. Examination of the antigenic structure of a 'street' virus isolate of measles virus revealed that it was antigenically distinct from wild type strains while similar to our laboratory-isolated variants suggesting that antigenic variation of measles was occurring in the 'wild.'.;The third part involved tryptic peptide analysis of the proteins of SSPE virus isolates to detect a biochemical marker for these mutants. This analysis revealed widespread antigenic and biochemical variation among these different SSPE strains. No biochemical marker was found. It suggests that SSPE viruses are subject to random mutation while in the persistent state.