Friend virus (FV) and lactate dehydrogenase-elevating virus (LDV) are endemic mouse viruses that can cause long-term chronic infections in mice. We found that numerous mouse-passaged FV isolates also contained LDV and that coinfection with LDV delayed FV-specific CD8 ؉ T-cell responses during acute infection. While LDV did not alter the type of acute pathology induced by FV, which was severe splenomegaly caused by erythroproliferation, the immunosuppression mediated by LDV increased both the severity and the duration of
SUMMARYCultures of starch-elicited peritoneal mouse macrophages in medium containing macrophage growth factor (MGF) were infected with lactate dehydrogenaseelevating virus (LDV) and, after various times in culture, LDV production was monitored as a function of time by infectivity titrations in mice, by measuring [3H]uridine incorporation into LDV RNA and extracellular LDV, by autoradiographic analysis of the proportion of productively infected cells and by electron microscopy. Regardless of the age of the cultures when infected with LDV, only a small proportion of the macrophages (generally between 3 and 20% of the total) became productively infected after a primary infection; maximum virus RNA synthesis and virus production occurred during the first 24 h after infection and then decreased precipitously. Productively infected macrophages could be readily recognized in electron micrographs of 24-h infected macrophage cultures and in sections of spleens from 24-h infected mice by characteristic morphological alterations. These consisted of formation of clusters of double-membrane vesicles with a diameter of 100 to 300 ~m, budding of nucleocapsids into vesicles with single membranes and accumulation of mature virions in these vesicles. One to 4 days later, however, such cells were no longer found in infected cultures or spleens of infected mice and superinfection did not restimulate LDV replication. Cultures established with macrophages from 1-day LDV-infected mice also did not support LDV replication. We conclude that LDV replication in cultures or mice is limited to a single cycle in a subpopulation of macrophages and that infection leads to cell death and rapid phagocytosis of the dead cells by the resistant, uninfected macrophages.
SUMMARYA primary infection of peritoneal macrophage cultures with the lactate dehydrogenase-elevating virus (LDV) results in productive infection of 3 to 20% of the cells. When cultures were incubated in the absence of macrophage growth factor (MGF), LDV production ceased after a single cycle, but in cultures in which macrophage replication was stimulated by the presence of MGF LDV production continued for several weeks at a low level, representing not more than 1% of that observed during the acute phase. Significant amounts of interferon were not present in either acutely or persistently infected cultures, and treatment of persistently infected cultures with anti-interferon globulin or superinfection with LDV did not significantly stimulate LDV replication. Macrophage cultures established with peritoneal macrophages from LDV-infected mice also showed only a low level of LDV replication and were resistant to superinfection by LDV. Mouse hepatitis virus, Semliki Forest virus and vesicular stomatitis virus, on the other hand, replicated normally in LDV-persistently infected macrophage cultures. LDV replication was relatively resistant to interferon whether added to the cultures or generated endogenously by infection with Newcastle disease virus or defective-interfering (DI) particles of vesicular stomatitis virus. Temperature-sensitive mutants or DI particles of LDV were not detected in LDV-persistently infected cultures or chronically infected mice. The results support our hypothesis that the decrease in LDV production in mice or macrophage cultures at the end of the acute phase results from the destruction of the subpopulation of macrophages that is permissive for LDV, and that the low level persistent infection involves the passage of the virus to new permissive cells that are generated continuously, although at a low rate, from non-permissive precursor cells.
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