(23) Specific Gamma 34.5 Gene Signatures Correlate with Neurovirulence in Neonatal HSV-2 Strains

Background: Each year, an estimated 14,000 newborns are infected with herpes simplex virus (HSV)-1 or HSV-2. In stark contrast to adult HSV infections, which are typically limited to recurrent lesions at mucosal surfaces, nearly half of neonatal HSV disease cases involve invasive infection of the central nervous system. Such infections often result in lifelong neurological deficits or in some cases immediate death.

Objectives: We aim to elucidate the factors that promote HSV infection of the neonatal brain, which are currently poorly understood.

Design/Methods: Recently, we showed that HSV-2 isolates collected from neonates with encephalitis are more neurovirulent in mice than those taken from neonates with skin-limited disease. We subsequently performed viral whole genome sequencing and a comparative genomics analysis to assess for variations unique to the most neurovirulent HSV-2 isolates.

Results: This analysis highlighted two variations of interest in the HSV-2 gamma 34.5 gene, which encodes the critical neurovirulence factor infected cell protein (ICP)34.5. While the orthologous HSV-1 ICP34.5 protein has been well studied, comparatively little is known about HSV-2 ICP34.5. It is known that alternative splicing of HSV-2 gamma 34.5 transcripts results in expression of a full-length ICP34.5 “alpha” isoform that partially resembles the HSV-1 protein, as well as a truncated ICP34.5 “beta” isoform with a unique C-terminus. Preliminary results indicate that gamma 34.5 variations in neurovirulent isolates result in increased expression of this beta isoform.

Conclusions: Ongoing work will determine how HSV-2 ICP34.5 isoform expression is regulated, as well as the binding targets of each isoform. Determining how HSV-2 ICP34.5 isoforms contribute to severe neurological infections in newborns could help to guide the development of new therapies that mitigate poor clinical outcomes.