Neuroinvasiveness of pseudorabies virus injected intracerebrally is dependent on viral concentration and terminal field density

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Abstract
Pseudorabies virus (PRV), a neurotropic swine α herpesvirus, has been used extensively for transneuronal analysis of multisynaptic circuitry after peripheral injection. In the present analysis, we examined the influence of viral concentration and neuronal architecture on the invasiveness, replication, and transynaptic passage of an attenuated strain of PRV (PRV-Bartha) injected into rat striatum. Different concentrations of PRV-Bartha were injected into the striatum at a constant rate of infusion (10 nl/minute), and animals were killed 50 hours later. Viral concentration was manipulated by either altering the volume of the inoculum (100, 50, 20 nl) or by diluting the inoculum within a constant volume of 100 nl. Immunohistochemical localization of infected neurons revealed dramatic differences in the progression of infection that were dependent directly on the concentration of injected virus. In every case, the pattern of infection was consistent with preferential uptake of virions by axon terminals and retrograde transynaptic passage of virus from the injection site. The known topographically organized corticostriatal projections permitted a precise definition of the zone of viral uptake. This analysis demonstrated that the “effective zone of viral uptake” (i.e., the zone within which viral uptake led to productive replication of virus) varied in relation to the concentration of injected virus, with the highest concentration of PRV invading terminals within a 500 μm radius of the canula. Concentration-dependent changes in the progression of retrograde transynaptic infection also were observed. The highest concentration of virus produced the most extensive infection. The distribution of infected neurons in these cases included those with known afferent projections to striatum as well as those that became infected by retrograde transynaptic infection. Lesser concentrations of PRV-Bartha produced an increasingly restricted infection of the same circuitry within the same postinoculation interval. It is noteworthy that neurons known to elaborate dense striatal terminal fields were less sensitive to reduction in viral concentration than those giving rise to terminal fields of lesser density. Collectively, the data indicate that the onset of viral replication after intracerebral injection of PRV is directly dependent on virus concentration and terminal field density at the site of virus injection. J. Comp. Neurol. 1999;407:438–452.