title: Herpes simplex virus 1 tropism for human sensory ganglion neurons in the severe combined immunodeficiency mouse model of neuropathogenesis.
abstract: The tropism of herpes simplex virus (HSV-1) for human sensory neurons infected in vivo was examined using dorsal root ganglion (DRG) xenografts maintained in mice with severe combined immunodeficiency (SCID). In contrast to the HSV-1 lytic infectious cycle in vitro, replication of the HSV-1 F strain was restricted in human DRG neurons despite the absence of adaptive immune responses in SCID mice, allowing the establishment of neuronal latency. At 12 days after DRG inoculation, 26.2% of human neurons expressed HSV-1 protein and 13.1% expressed latency-associated transcripts (LAT). Some infected neurons showed cytopathic changes, but HSV-1, unlike varicella-zoster virus (VZV), only rarely infected satellite cells and did not induce fusion of neuronal and satellite cell plasma membranes. Cell-free enveloped HSV-1 virions were observed, indicating productive infection. A recombinant HSV-1-expressing luciferase exhibited less virulence than HSV-1 F in the SCID mouse host, enabling analysis of infection in human DRG xenografts for a 61-day interval. At 12 days after inoculation, 4.2% of neurons expressed HSV-1 proteins; frequencies increased to 32.1% at 33 days but declined to 20.8% by 61 days. Frequencies of LAT-positive neurons were 1.2% at 12 days and increased to 40.2% at 33 days. LAT expression remained at 37% at 61 days, in contrast to the decline in neurons expressing viral proteins. These observations show that the progression of HSV-1 infection is highly restricted in human DRG, and HSV-1 genome silencing occurs in human neurons infected in vivo as a consequence of virus-host cell interactions and does not require adaptive immune control.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA. zerboni@stanford.edu
authors.forename: Leigh
authors.initials: L
authors.lastname: Zerboni
authors.forename: Xibing
authors.initials: X
authors.lastname: Che
authors.forename: Mike
authors.initials: M
authors.lastname: Reichelt
authors.forename: Yanli
authors.initials: Y
authors.lastname: Qiao
authors.forename: Haidong
authors.initials: H
authors.lastname: Gu
authors.forename: Ann
authors.initials: A
authors.lastname: Arvin
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D005727:Ganglia, Spinal / Q000473:pathology / Q000821:virology*; D015870:Gene Expression; D006561:Herpes Simplex / Q000188:drug therapy / Q000378:metabolism / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014645:Herpesvirus 3, Human; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis; D051379:Mice; D016513:Mice, SCID; D027161:Satellite Cells, Perineuronal / Q000821:virology; D016511:Severe Combined Immunodeficiency / Q000821:virology*; D014183:Transplantation, Heterologous; D000077483:Valacyclovir; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D014764:Viral Proteins / Q000378:metabolism; D056189:Viral Tropism; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D014764:Viral Proteins; D008156:Luciferases; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir