Genotypic and phenotypic diversity within the neonatal HSV-2 population

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Abstract
More than 14,000 neonates are infected with herpes simplex virus (HSV) annually. Approximately half display manifestations limited to the skin, eyes, or mouth (SEM disease). The rest develop invasive infections that spread to the central nervous system (CNS disease or encephalitis) or systemically (disseminated disease). Invasive HSV disease is associated with significant morbidity and mortality, but viral and host factors that predispose neonates to these forms are unknown. To define viral diversity within the infected neonatal population, we evaluated ten HSV-2 isolates from newborns with a range of clinical presentations. To assess viral fitness independent of host immune factors, we measured viral growth characteristics in cultured cells and found diverse in vitro phenotypes. Isolates from neonates with CNS disease were associated with larger plaque size and enhanced spread, with isolates from cerebrospinal fluid (CSF) exhibiting the most robust growth. We sequenced complete viral genomes of all ten neonatal viruses, providing new insights into HSV-2 genomic diversity in this clinical setting. We found extensive inter-host and intra-host genomic diversity throughout the viral genome, including amino acid differences in more than 90% of the viral proteome. The genes encoding glycoprotein G (gG, US4), gI (US7), gK (UL53), and viral proteins UL8, UL20, UL24, and US2 contained variants that were found in association with CNS isolates. Many of these viral proteins are known to contribute to cell spread and neurovirulence in mouse models of CNS disease. This study represents the first application of comparative pathogen genomics to neonatal HSV disease. Importance: Herpes simplex virus (HSV) causes invasive disease in half of infected neonates, resulting in significant mortality and permanent cognitive morbidity. The factors that contribute to invasive disease are not understood. This study reveals diversity among HSV isolates from infected neonates, and makes the first associations between viral genetic variations and clinical disease manifestations. We found that viruses isolated from newborns with encephalitis show enhanced spread in culture. These viruses contain protein-coding variations not found in viruses causing non-invasive disease. Many of these variations are found in proteins known to impact neurovirulence and viral spread between cells. This work advances our understanding of HSV diversity in the neonatal population and how it may impact disease outcome.
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