title: The herpes simplex virus type 1 latency-associated transcript can protect neuron-derived C1300 and Neuro2A cells from granzyme B-induced apoptosis and CD8 T-cell killing.
abstract: The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) is the only HSV-1 gene transcript abundantly expressed throughout latency. LAT null mutants have a significantly reduced reactivation phenotype. LAT's antiapoptosis activity is the major LAT factor involved in supporting the wild-type reactivation phenotype. During HSV-1 latency, some ganglionic neurons are surrounded by CD8 T cells, and it has been proposed that these CD8 T cells help maintain HSV-1 latency by suppressing viral reactivations. Surprisingly, despite injection of cytotoxic lytic granules by these CD8 T cells into latently infected neurons, neither apoptosis nor neuronal cell death appears to occur. We hypothesized that protection of latently infected neurons against cytotoxic CD8 T-cell killing is due to LAT's antiapoptosis activity. Since CD8 T-cell cytotoxic lytic granule-mediated apoptosis is critically dependent on granzyme B (GrB), we examined LAT's ability to block GrB-induced apoptosis. We report here that (i) LAT can interfere with GrB-induced apoptosis in cell cultures, (ii) LAT can block GrB-induced cleavage (activation) of caspase-3 both in cell culture and in a cell-free in vitro cell extract assay, and (iii) LAT can protect C1300 and Neuro2A cells from cytotoxic CD8 T-cell killing in vitro. These findings support the hypothesis that LAT's antiapoptosis activity can protect latently infected neurons from being killed by CD8 T-cell lytic granules in vivo.
authors.affiliation: University of California, Irvine, Dept. of Ophthalmology, Orange, CA 92868, USA.
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Jiang
authors.forename: Aziz Alami
authors.initials: AA
authors.lastname: Chentoufi
authors.forename: Chinhui
authors.initials: C
authors.lastname: Hsiang
authors.forename: Dale
authors.initials: D
authors.lastname: Carpenter
authors.forename: Nelson
authors.initials: N
authors.lastname: Osorio
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Fraser
authors.forename: Clinton
authors.initials: C
authors.lastname: Jones
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wechsler
mesh_terms: D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D053804:Granzymes / Q000235:genetics / Q000276:immunology*; D006561:Herpes Simplex / Q000201:enzymology / Q000276:immunology* / Q000503:physiopathology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000821:virology; D014775:Virus Activation
chemical_list: D035683:MicroRNAs; C477253:latency associated transcript, herpes simplex virus-1; D053804:Granzymes