TY - JOUR
T1 - Genotypic and phenotypic diversity of herpes simplex virus 2 within the infected neonatal population
AU - Akhtar, Lisa N.
AU - Bowen, Christopher D.
AU - Renner, Daniel W.
AU - Pandey, Utsav
AU - Della Fera, Ashley N.
AU - Kimberlin, David W.
AU - Prichard, Mark N.
AU - Whitley, Richard J.
AU - Weitzman, Matthew D.
AU - Szpara, Moriah L.
N1 - Funding Information:
This research was supported by NIAID grant 1R21AI140443 (M.L.S. and M.D.W.), with additional support from the following: startup funds from the Pennsylvania State University (M.L.S.), a CURE grant from the Pennsylvania Department of Health (M.L.S.), a grant from the National Institutes of Health (NS082240 to M.D.W.), and NICHD Pediatric Scientist Development grant K12-HD000850 (L.N.A.). The published NIAID CASG clinical studies of neonatal HSV infection were funded by a contract (N01-AI-62554) with the NIAID Development and Applications Branch and by grants from the General Clinical Research Center Program (RR-032) and the state of Alabama.
Publisher Copyright:
© 2019 Akhtar et al.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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 throughout the infected neonate (disseminated disease). Invasive HSV disease is associated with significant morbidity and mortality, but the viral and host factors that predispose neonates to these forms are unknown. To define viral diversity within the infected neonatal population, we evaluated 10 HSV-2 isolates from newborns with a range of clinical presentations. To assess viral fitness independently 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 the isolates from cerebrospinal fluid (CSF) exhibiting the most robust growth. We sequenced complete viral genomes of all 10 neonatal viruses, providing new insights into HSV-2 genomic diversity in this clinical setting. We found extensive interhost and intrahost 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), glycoprotein I (gI; US7), and glycoprotein K (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 report represents the first application of comparative pathogen genomics to neonatal HSV disease.
AB - 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 throughout the infected neonate (disseminated disease). Invasive HSV disease is associated with significant morbidity and mortality, but the viral and host factors that predispose neonates to these forms are unknown. To define viral diversity within the infected neonatal population, we evaluated 10 HSV-2 isolates from newborns with a range of clinical presentations. To assess viral fitness independently 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 the isolates from cerebrospinal fluid (CSF) exhibiting the most robust growth. We sequenced complete viral genomes of all 10 neonatal viruses, providing new insights into HSV-2 genomic diversity in this clinical setting. We found extensive interhost and intrahost 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), glycoprotein I (gI; US7), and glycoprotein K (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 report represents the first application of comparative pathogen genomics to neonatal HSV disease.
KW - Comparative genomics
KW - Herpes simplex virus
KW - Human herpesvirus 2
KW - Minor variants
KW - Neonatal
KW - Viral spread
UR - http://www.scopus.com/inward/record.url?scp=85062389274&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062389274&partnerID=8YFLogxK
U2 - 10.1128/mSphere.00590-18
DO - 10.1128/mSphere.00590-18
M3 - Article
C2 - 30814317
AN - SCOPUS:85062389274
VL - 4
JO - mSphere
JF - mSphere
SN - 2379-5042
IS - 1
M1 - e00590-18
ER -