Identification of a nonproductive, cell-associated form of measles virus by its resistance to inhibition by recombinant human interferon

Abstract

Subacute sclerosing panencephalitis (SSPE) is a fatal disease in children and young adults that is caused by persistent infection of the central nervous system (CNS) by a nonproductive, cell-associated form of measles virus. Using an experimental model for SSPE (LEC viral strain in newborn hamsters), we have shown previously that establishment of such CNS infections involves selective elimination from the CNS of productively infected cells by host defensive mechanisms, coupled with the selective sparing of cells carrying nonproductive viral forms. That interferon (IFN) may play a role in this process was suggested by the disappearance of productively infected cells from the CNS tissues prior to the appearance of antiviral antibodies and by the demonstration of cell-associated, IFN-resistant viral variants in the virus stocks that were used. Results of this study support these conclusions by showing that similar IFN-resistant viral variants are present in the HBS strain of SSPE-derived measles virus and that these variants, in the presence of IFN, have properties that are similar to those of naturally occurring cell-associated'strains of SSPE viruses, e.g., DR, IP3, and Biken. These IFN-resistant forms of HBS virus were isolated and were shown to maintain their resistance to inhibition by IFN after cloning. However, on removal of IFN, they reverted to productive forms similar to the parental HBS virus. The potential role of such viral forms in the pathogenesis of SSPE is discussed.

Identification of interferon-resistant subpopulations in several strains of measles virus: positive selection by growth of the virus in brain tissue

“…The hypothesis being tested in these studies centers upon the presence of IFN-resistant viral subpopulations in most or all strains of measles virus. One direct test of this possibility would be to subject several independent strains of virus to the same experimental protocol used previously with the LEC and HBS strains of virus (15,16). To this end, cell monolayers were pretreated with medium containing various concentrations of IFN and then infected with several strains of measles virus.…”

“…These cultures were then observed daily for at least 2 weeks for the appearance of viral CPE. This procedure provides increased sensitivity compared with the methods used previously (15,16).…”

“…inducing a self-limited and cell-associated infection in the presence of interferon (IFN) (15,16). The similarities between this type of viral replication and the properties of several cell-associated strains of SSPE measles virus (9, 24, 42, 45) led to the hypothesis that the restricted viral protein expression seen in the CNS tissues of SSPE patients results from the chronic production of enough IFN to suppress all of the virus present except the resistant forms such as those identified in the LEC and HBS virus strains.…”

“…Recombinant DNA-derived hybrid human IFN-a was obtained from Hoffman-LeRoche Inc., Nutley, N.J. Procedures involved in its use were identical to those described previously (15,16). In summary, cells were treated with medium containing the appropriate concentration of IFN for 24 h prior to infection.…”

“…Quantitative assessment of viral CPE in infected-cell cultures. The procedure for quantitative assessment of viral cytopathic effects (CPE) in infected-cell cultures has been described in detail previously (16). Briefly, cell monolayers were divided into quadrants, and at least 10 microscopic fields per quadrant were examined for viral CPE by phasecontrast microscopy.…”