The lactate dehydrogenase-elevating virus (LDV) possesses a number of unique properties which makes it an ideal model system for studying mechanisms of virus persistence and induction of paralytic disease by a virus that normally causes only a benign infection. LDV replicates only in a subpopulation of macrophages in the mouse. Upon primary infection, these cells seem to succumb to productive infection resulting in extensive viremia, transient production of interferon, and elevation of certain enzymes in the blood. This acute infection invariably progresses into a life long, persistent infection associated with low virus production and an immune response to the virus. The persistence seems to be maintained by the continuous transfer of the virus to newly formed permissive macrophages. A poor neutralizing capacity of mouse antibody, immune enhancement of infectivity and the development of antigenic variants may be factors contributing to persistence. Infection of most mouse strains does not result in clinical disease. The exception are C58 and AKR mice in which an acute infection induces a rapid and fatal polioencephalomyelitis provided the mice have passed a certain age and are immunosuppressed. Our main goal at present is to sequence the entire genome of LDV. cDNA has been cloned in pUC19 (clones range from 50 to 2500 bp), subcloned into M13 bacteriophage and is being sequenced by the dideoxynucleodite chain termination method. Such sequence data will be very valuable in combination with monoclonal antibodies, which are presently being isolated in future studies of the molecular basis of antigenic variants of LDV and variants differing in neurovirulence, of the epitopes of the LDV glycoprotein interacting with neutralizing antibodies and of the nature and function of the nonstructural proteins of LDV, which potentially account for 90% of the coding capacity of the genome. In addition, we plan to identify the cells in the mouse that support LDV replication during the acute and persistent phases of infection by combined in situ hybridization and immunocytochemistry of tissue and whole body sections. The sections will be sequentially incubated with biotinylated mouse anti-LDV IgG, avidine-peroxidase complex and peroxidase substrate and then hybridized with 125I-labeled cDNA probes. We will also attempt to develop a cell culture line permissive for LDV replication for further biochemical studies of LDV replication and the in vitro titration of infectious LDV.
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