Selective antibody neutralization prevents neuropathogenic lactate dehydrogenase-elevating virus from causing paralytic disease in immunocompetent mice

Neuropathogenic lactate dehydrogenase-elevating viruses (LDV) cytocidally i nfect anterior horn neurons in C58 and AKR mice via interaction with endoge nous murine retroviruses to cause a paralytic disease; age-dependent poliom yelitis (ADPM). The induction of ADPM requires a suppressed host immune sys tem as a result of old age, genetic defects (such as nude mice) or any immu nosuppressive treatment. Previous results have shown that the infection of anterior horn neurons by neuropathogenic LDV isolates and the subsequent de velopment of ADPM are prevented by anti-LDV antibodies either induced activ ely during infection or when passively administered. However, the mechanism of protection was unclear since both neutralizing and nonneutralizing poly clonal antibodies seemed protective, whereas only neutralizing monoclonal a ntibodies were protective. Furthermore, the protection of motor neurons fro m infection occurred in the absence of any apparent effect on LDV replicati on in a subpopulation of macrophages known to be the primary permissive hos t cells. These paradoxes have now been resolved. We have recently reported that the neuropathogenic LDV isolates contain both neuropathogenic and non- neuropathogenic quasispecies that differ in their ability to establish a hi gh viremia persistent infection. Using biological clones of both neuropatho genic and non-neuropathogenic quasispecies; we now demonstrate that both re plicate in the same subpopulation of permissive macrophages, but that the n europathogenic quasispecies are about 100 times more susceptible to in vitr o antibody neutralization than the non-neuropathogenic ones, and that antib odies that neutralize the neuropathogenic but not the non-neuropathogenic q uasispecies develop as soon as 7 days after infection with neuropathogenic LDVs and selectively suppress the replication of the neuropathogenic LDVs i n vivo in FVB, BALB/c, C57 BL/6 and C58 mice. The previously observed lack of neutralizing effect of early polyclonal anti-LDV antibodies and the appa rent ineffective antibody control of LDV replication in macrophages were du e to outgrowth of the non-neuropathogenic quasispecies that are also presen t in the neuropathogenic LDV inoculum and are highly resistant to antibody neutralization. Using cloned neuropathogenic LDV quasispecies, we demonstra te a clear relationship in the development of neutralizing antibodies, repl ication suppression of the neuropathogenic LDVs and the prevention of ADPM in C58 mice. Our results therefore establish an inseparable relationship be tween the neuron-protective effect of an antibody and its neutralization of the neuropathogenic LDV quasispecies and explain why neuropathogenic LDVs cause paralytic disease only in immunosuppressed mice.