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Infection with helper-free, defective MAIDS murine leukemia virus (MuLV) caused a rapid polyclonal activation of B cells in 0.75-, 2-, and 6-month-old C57L/J mice (H-2b, Fv-1n/n), similar to that in C57BL/6 mice (H-2b, Fv-1b/b), which was recognized by elevated plasma immunoglobulin concentrations. However, changes in plasma immunoglobulin levels differed in C57BL/J and C57BL/6 mice. In C57L/J mice, infection resulted in a rapid increase in plasma IgM and IgG2a, and the elevation of IgG2a persisted undiminished for 21 weeks. Levels of IgG2b also became slightly elevated, but those of IgG1 and IgG3 were not significantly affected. Plasma of 6 to 7-month-old C57BL/6 mice contained already high levels of IgM (30-40 mg/ml), which persisted undiminished in uninfected mice but decreased progressively in infected mice to 10% of the original concentration during 25 weeks of observation. In C57BL/6 mice, plasma IgG1 and IgG2b as well as IgG2a became similarly elevated after infection but also only transiently. Their levels began to decrease progressively about 10 weeks after infection and fell to far below the maximum concentration observed. The drastic loss of plasma IgM and IgGs observed in C57BL/6 mice during the later stages of MAIDS MuLV infection did not seem to be a consequence of the polyclonal activation of B cells per se but seemed to reflect additional immunological abnormalities arising in infected C57BL/6 but not C57L/J mice. In both mouse strains these changes in plasma Ig levels correlated with the formation of Ig-containing immune complexes that bound to high-affinity, protein-binding ELISA plates in the absence of antigen coating, which may represent unusual forms of self-antigen-antibody complexes.

Concentrations of IgM and IgG isotypes were determined by capture ELISA in plasma of Swiss, BALB/c and C58/M mice. Plasma IgG isotype concentrations, especially of IgM, IgG1 and IgG2a, varied considerably between mouse strains, batches of mice of the same strain and individual mice and as a function of age. Infection of the mice with LDV, which is known to replicate primarily in a subpopulation of macrophages, consistently resulted in a rapid elevation of plasma IgG2a (or of IgG2b in some Swiss nu/+ mice), but no plasma IgG increases were observed in mice immunized with inactivated LDV. Plasma IgG2a elevation after LDV infection was greatly delayed and reduced by depletion of the mice of CD4+, but not of CD8+, T cells by administration of protein-G-purified anti-CD4 or anti-CD8 mAbs, and completely inhibited by repeated treatment of the mice with cyclophosphamide. Treatment with anti-CD4 mAbs, or cyclophosphamide also greatly reduced the production of anti-LDV antibodies, while not significantly affecting the replication of LDV in these mice. Nude Swiss mice also failed to produce anti-LDV antibodies, though supporting normal LDV replication. Plasma IgM, IgG1, IgG2a and IgG2b levels increased in LDV-infected nu/nu mice, but similar changes were observed in uninfected mice. The results indicate that the LDV-induced polyclonal activation of B cells requires productive LDV infection of mice and is, at least partly, dependent on functioning CD4+ cells. They suggest that productive infection of the LDV-permissive subpopulation of macrophages leads to the activation of CD4+ T lymphocytes of subset 1 and their Spleen cells from 5-day LDV-infected BALB/c mice incorporated [3H]thymidine 2-3 times more rapidly in vitro than spleen cells from companion uninfected mice, whereas their responses to concanavalin A and lipopolysaccharide were reduced 60-70%.

Maximum plasma titers (10(9)-10(10) ID50/ml) of lactate dehydrogenase-elevating virus (LDV) in mice are observed one day after infection, but then decrease 4-5 log during the next 5 weeks to attain a persistent steady-state level for the remainder of the life of the animal. The decrease in plasma LDV level during the first 5 weeks after infection and long-term viremia were not affected by lethal X-irradiation of the mice, daily injections of cyclosporin A or depletion of the mice of T cells by treatment with anti-CD4, anti-CD8, or anti-Thy1.2 monoclonal antibodies, although these treatments inhibited the formation of anti-LDV antibodies. LDV viremia was also the same in nu/nu and nu/+ Swiss mice, though the former did not mount an anti-LDV immune response, while the latter did. The appearance of anti-LDV neutralizing antibodies in infected mice 1-2 months after infection or the injection of infected mice with high doses of anti-LDV neutralizing monoclonal antibodies also did not affect the level of LDV viremia. Repeated treatments of infected mice with either cyclophosphamide or dexamethasone caused 1-2 log increases in plasma LDV titers. Although cyclophosphamide treatment prevented the formation of anti-LDV antibodies, dexamethasone caused an increase in plasma LDV levels without affecting anti-LDV antibody formation. We conclude that an anti-LDV immune response does not play a significant role in controlling LDV replication in mice. The data support the view that within 1 day after infection of a mouse, all LDV-permissive macrophages, which appear to be the only cells supporting LDV replication in the mouse, are destroyed as a result of a cytocidal infection by LDV. Subsequently, LDV replication is limited by the rate of generation of new permissive macrophages. The steady-state viremia attained about 5 weeks after infection reflects a balance between LDV replication in permissive macrophages as they arise and LDV inactivation and clearance.