A herpes simplex virus DNA polymerase mutation that specifically attenuates neurovirulence in mice

Herpes simplex virus can infect the mammalian brain causing lethal encephal itis (neurovirulence). Previously herpes simplex virus mutants that are att enuated for neurovirulence have exhibited defects in replication in brain a nd/or blocks to replication in neuronal cells. We investigated the attenuat ion of neurovirulence of mutant PAA(r)5, which exhibits resistance to antiv iral drugs due to altered viral DNA polymerase. Following intracerebral ino culation of 7-week-old CD1 mice, PAA(r)5 was 30-fold attenuated for neurovi rulence compared to its wild-type parent. A drug-sensitive virus derived by marker rescue with DNA polymerase gene sequences exhibited neurovirulence that was essentially indistinguishable from that of wild-type virus, demons trating that attenuation was due to a polymerase mutation. PAA(r)5 replicat ed in brain similarly to wild-type virus unlike another polymerase mutant, 615.8, that exhibited a similar degree of attenuation. The attenuation of P AA(r)5 was not associated with altered particle to PFU ratios nor with any obvious reductions in viral antigen expression in neurons, spread, histopat hology, or TUNEL staining suggestive of apoptotic cells. Thus PAA(r)5 diffe rs from other mutants that are attenuated for neurovirulence. Understanding how a polymerase mutation specifically attenuates neurovirulence may shed light on how herpes simplex virus can cause lethal encephalitis. (C) 1998 A cademic Press.