NEUROINVASIVE PROPERTIES OF HERPES-SIMPLEX VIRUS TYPE-1 GLYCOPROTEIN VARIANTS ARE CONTROLLED BY THE IMMUNE-RESPONSE

Neuroinvasiveness is a property central to the pathogenesis of herpes simplex virus (HSV) and most isolates demonstrate this property. Excep tions are HSV strains KOS and ANG, for which we have previously shown that the non-neuroinvasive phenotype is referable to single amino acid changes in glycoprotein D for ANG or glycoprotein B for KOS. Because glycoproteins B and D are immunologically significant, the possibility that the phenotype has an immunologic basis was examined. Nonimmunosu ppressed mice could not be killed with any dose of these non-neuroinva sive viruses after footpad inoculation, but in cyclophosphamide-suppre ssed animals, the ratios of plaque-forming units to ID50 decreased by at least four orders of magnitude to levels comparable with that of AN G-path, a neuroinvasive derivative of ANC, KOS and ANC induced a more rapid circulating neutralizing Ab response than did ANG-path, and mice were protected when these agents were co-infected with the neuro-inva sive strain. The noninvasive viruses engendered an enhanced mononuclea r cell infiltrate in infected spinal ganglia which consisted of increa sed numbers of CD4(+) and CD8(+) T cells and an increased production a nd secretion of IgG. HSV-specific Ab-secreting cells were also observe d. In addition, passive transfer of anti-HSV mouse serum protected imm unosuppressed mice from lethal HSV challenge. Selective in vivo deplet ion of T lymphocytes increased the detectable levels of both KOS and A NG viruses in the spinal ganglia at 6 days postinfection, but it did n ot alter the ratios of plaque-forming units to LD(50) or affect the HS V-induced increase in ganglionic IgG. Taken together, these data indic ate that in these systems there is an immunologic basis for the contro l of HSV-1 neuroinvasiveness and that humoral, rather than cell-mediat ed immunity, is playing the major role.