Evasion of APOBEC1-mediated Intrinsic Immunity by a Herpesvirus Uracil DNA Glycosylase Is a Determinant of Viral Encephalitis

Herpes simplex virus 1 (HSV-1) is the most common cause of viral encephalitis, which can be lethal or result in severe neurological defects, even when treated with antiviral therapy. We demonstrated that activation of HSV-1 uracil-DNA glycosylase (vUNG) by phosphorylation, essential for its enzymatic activity, counteracted APOBEC1 to promote viral replication and encephalitis in the central nervous system (CNS) of mice. The activation of vUNG protected HSV-1 genomes from APOBEC1-mediated DNA editing, allowing efficient viral replication to occur. The presence of APOBEC1 markedly improved lethal encephalitis in mice infected with an HSV-1 mutant carrying a mutation in the phosphorylation site and an UNG inhibitor protected wild-type HSV-1-infected mice from lethal encephalitis. These findings re-define vUNG as an important factor that allows evasion from intrinsic anti-viral immunity mediated by APOBEC1 in the CNS, and suggest a new therapeutic approach for the treatment of fetal and critical HSV-1 encephalitis.