SUPPRESSION OF LYMPHOCYTIC CHORIOMENINGITIS VIRUS-INDUCED GROWTH-HORMONE DEFICIENCY SYNDROME BY DISEASE-NEGATIVE VIRUS VARIANTS

Populations of RNA viruses consist of heterogeneous mixtures of relate d genomes (quasispecies). Isolation of variants present at low levels within a population can result in clonal virus populations which displ ay markedly different phenotypes upon infection of the host. The mecha nisms by which these variants are maintained within the original quasi species are not understood. Certain strains of lymphocytic choriomenin gitis virus (LCMV) cause a growth hormone deficiency syndrome (GHDS) w hen inoculated into newborn C3H/St mice while others do not. We have p reviously described the isolation of virus clones from the GHDS-negati ve WE strain of LCMV which differ in their ability to cause GHDS. To i nvestigate how disease-positive clones can remain hidden within a dise ase-negative parental population, we examined whether infection with m ixtures of the GHDS-negative (WE c54) and GHDS-positive (WE c2.5) clon es could cause GHDS. Neonatal C3H/ST mice infected with 100:1 or 10:1 ratios of WE c54 to WE c2.5 did not develop the syndrome, while animal s infected with 1:1 or lower ratios did. Development of GHDS correlate d with the extent to which the GH-producing cells of the anterior pitu itary were infected. These data indicate that a large excess of diseas e-negative clones can restrict the replication of disease-positive clo nes in GH-producing cells, thus preventing the onset of GHDS. In addit ion, our results indicate that a threshold for phenotypic dominance ex ists. Interestingly, WE c54 did not entirely outcompete WE c2.5 in mic e infected with the 100:1 ratio, suggesting a mechanism whereby pathog enic viruses can he maintained within a nonpathogenic viral population . (C) 1996 Academic Press, Inc.