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Background Neonatal HSV infection is associated with significant morbidity and mortality. Neonates with HSV infection can present with skin, eye, and mouth (SEM), central nervous system disease (CNS), and disseminated disease (DIS). We hypothesize that host immune responses may contribute to differences in disease presentation and outcomes. To address this knowledge gap, we analyzed host transcriptional immune profiles of neonates with HSV infection. Methods Infants &amp;lt; 6 weeks of age (24 (86%) &amp;lt; 4 weeks; 4 (14%) 4-6 weeks old) with neonatal HSV, and healthy infant controls (HC) were enrolled at Children’s Medical Center (Dallas, TX), and Nationwide Children’s Hospital (Columbus, OH) from 2007-2018. Whole blood samples were analyzed by RNA-seq. Modular analyses were performed to identify the immune pathways that were activated or suppressed according to each HSV disease category. Results Of the 28 infants with HSV infection, 9 had SEM (median [IQR] age: 14 [14-28] days), 10 CNS (age: 18 [15-29] days), and 9 DIS (age: 10 [7-10] days). Three infants with DIS died within 5 days of diagnosis. Statistical group comparisons between 13 HC and 18 infants with HSV disease (training set) identified 1,322 differentially expressed genes (neonatal HSV biosignature). This biosignature was validated in the remaining 10 infants with HSV disease (test set), and was characterized by significant overexpression of interferon (INF), inflammation, neutrophils, and monocyte genes and under-expression of T-cell genes. Further analysis according to HSV disease category confirmed overexpression of neutrophil and inflammation genes in infants with SEM, CNS and DIS (Fig 1). On the other hand, overexpression of INF and plasma cell genes, and further suppression of monocytes, cytotoxic/NK cells, and T-cell genes were only evident in children with DIS. Fig 1: Modular immune pathways according to HSV disease category Modules are groups of genes that shared a similar function. Each dot represents a transcriptional module with red indicating overexpression and blue underexpression in relation to healthy controls. The number and color intensity on the dot indicate the percentage of differentially expressed transcripts within a module. SEM: skin, eye mouth; CNS: central nervous system; DIS: disseminated HSV disease. Conclusion Transcriptional profiles of infants with HSV infection exhibited marked activation of the innate immune response irrespective of disease classification. Children with DIS showed more profound dysregulation and suppression of cellular immune responses. Transcriptional profiling may aid unravel mechanisms associated with clinical outcomes in neonatal HSV and inform future therapeutic and preventive strategies. Disclosures Octavio Ramilo, MD, Adagio (Consultant)Bill &amp; Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck (Consultant, Grant/Research Support)NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member)

82. Blood Gene Expression Profiles in Neonates with Herpes Simplex Virus (HSV) Infection