title: A limited innate immune response is induced by a replication-defective herpes simplex virus vector following delivery to the murine central nervous system.
abstract: Herpes simplex virus type 1 (HSV-1)-based vectors readily transduce neurons and have a large payload capacity, making them particularly amenable to gene therapy applications within the central nervous system (CNS). Because aspects of the host responses to HSV-1 vectors in the CNS are largely unknown, we compared the host response of a nonreplicating HSV-1 vector to that of a replication-competent HSV-1 virus using microarray analysis. In parallel, HSV-1 gene expression was tracked using HSV-specific oligonucleotide-based arrays in order to correlate viral gene expression with observed changes in host response. Microarray analysis was performed following stereotactic injection into the right hippocampal formation of mice with either a replication-competent HSV-1 or a nonreplicating recombinant of HSV-1, lacking the ICP4 gene (ICP4-). Genes that demonstrated a significant change (P < .001) in expression in response to the replicating HSV-1 outnumbered those that changed in response to mock or nonreplicating vector by approximately 3-fold. Pathway analysis revealed that both the replicating and nonreplicating vectors induced robust antigen presentation but only mild interferon, chemokine, and cytokine signaling responses. The ICP4- vector was restricted in several of the Toll-like receptor-signaling pathways, indicating reduced stimulation of the innate immune response. These array analyses suggest that although the nonreplicating vector induces detectable activation of immune response pathways, the number and magnitude of the induced response is dramatically restricted compared to the replicating vector, and with the exception of antigen presentation, host gene expression induced by the nonreplicating vector largely resembles mock infection.
authors.affiliation: Departments of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida 32610-0266, USA.
authors.forename: Zane
authors.initials: Z
authors.lastname: Zeier
authors.forename: J Santiago
authors.initials: JS
authors.lastname: Aguilar
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lopez
authors.forename: G B
authors.initials: GB
authors.lastname: Devi-Rao
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Watson
authors.forename: Henry V
authors.initials: HV
authors.lastname: Baker
authors.forename: Edward K
authors.initials: EK
authors.lastname: Wagner
authors.forename: David C
authors.initials: DC
authors.lastname: Bloom
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D002490:Central Nervous System / Q000276:immunology* / Q000821:virology; D005260:Female; D015967:Gene Expression Regulation, Viral; D017781:Genes, Immediate-Early / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000276:immunology*; D007763:Lac Operon / Q000235:genetics; D051379:Mice; D008845:Microinjections; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication
chemical_list: D039481:CD11b Antigen; D039521:CD11c Antigen