Suppression of lymphocytic choriomeningitis virus--induced growth hormone deficiency syndrome by disease-negative virus variants.
Populations of RNA viruses consist of heterogeneous mixtures of related genomes (quasispecies). Isolation of variants present at low levels within a population can result in clonal virus populations which display markedly different phenotypes upon infection of the host. The mechanisms by which these variants are maintained within the original quasispecies are not understood. Certain strains of lymphocytic choriomeningitis virus (LCMV) cause a growth hormone deficiency syndrome (GHDS) when inoculated into newborn C3H/St mice while others do not. We have previously described the isolation of virus clones from the GHDS-negative WE strain of LCMV which differ in their ability to cause GHDS. To investigate how disease-positive clones can remain hidden within a disease-negative parental population, we examined whether infection with mixtures of the GHDS-negative (WE c54) and GHDS-positive (WE c2.5) clones 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 animals infected with 1:1 or lower ratios did. Development of GHDS correlated with the extent to which the GH-producing cells of the anterior pituitary were infected. These data indicate that a large excess of disease-negative clones can restrict the replication of disease-positive clones in GH-producing cells, thus preventing the onset of GHDS. In addition, our results indicate that a threshold for phenotypic dominance exists. Interestingly, WE c54 did not entirely outcompete WE c2.5 in mice infected with the 100:1 ratio, suggesting a mechanism whereby pathogenic viruses can be maintained within a nonpathogenic viral population.
Teng
M N
MN
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.
Oldstone
M B
MB
de la Torre
J C
JC
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D013006:Growth Hormone / Q000172:deficiency*; D008216:Lymphocytic Choriomeningitis / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D051379:Mice; D008809:Mice, Inbred C3H; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000032:analysis; D013577:Syndrome
D012367:RNA, Viral; D013006:Growth Hormone