title: The herpes simplex virus type 1 latency-associated transcript inhibits phenotypic and functional maturation of dendritic cells.
abstract: We recently found that the herpes simplex virus-1 (HSV-1) latency-associated transcript (LAT) results in exhaustion of virus-specific CD8⁺ T cells in latently-infected trigeminal ganglia (TG). In this study we sought to determine if this impairment may involve LAT directly and/or indirectly interfering with DC maturation. We found that a small number of HSV-1 antigen-positive DCs are present in the TG of latently-infected CD11c/eYFP mice; however, this does not imply that these DCs are acutely or latently infected. Some CD8⁺ T cells are adjacent to DCs, suggesting possible interactions. It has previously been shown that wild-type HSV-1 interferes with DC maturation. Here we show for the first time that this is associated with LAT expression, since compared to LAT⁻ virus: (1) LAT⁺ virus interfered with expression of MHC class I and the co-stimulatory molecules CD80 and CD86 on the surface of DCs; (2) LAT⁺ virus impaired DC production of the proinflammatory cytokines IL-6, IL-12, and TNF-α; and (3) DCs infected in vitro with LAT⁺ virus had significantly reduced the ability to stimulate HSV-specific CD8⁺ T cells. While a similar number of DCs was found in LAT⁺ and LAT⁻ latently-infected TG of CD11c/eYFP transgenic mice, more HSV-1 Ag-positive DCs and more exhausted CD8 T cells were seen with LAT⁺ virus. Consistent with these findings, HSV-specific cytotoxic CD8⁺ T cells in the TG of mice latently-infected with LAT⁺ virus produced less IFN-γ and TNF-α than those from TG of LAT⁻-infected mice. Together, these results suggest a novel immune-evasion mechanism whereby the HSV-1 LAT increases the number of HSV-1 Ag-positive DCs in latently-infected TG, and interferes with DC phenotypic and functional maturation. The effect of LAT on TG-resident DCs may contribute to the reduced function of HSV-specific CD8⁺ T cells in the TG of mice latently infected with LAT⁺ virus.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, School of Medicine, University of California-Irvine, Irvine, California, USA.
authors.forename: Aziz Alami
authors.initials: AA
authors.lastname: Chentoufi
authors.forename: Xavier
authors.initials: X
authors.lastname: Dervillez
authors.forename: Gargi
authors.initials: G
authors.lastname: Dasgupta
authors.forename: Chelsea
authors.initials: C
authors.lastname: Nguyen
authors.forename: Khaled W
authors.initials: KW
authors.lastname: Kabbara
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Jiang
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Nesburn
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wechsler
authors.forename: Lbachir
authors.initials: L
authors.lastname: Benmohamed
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002454:Cell Differentiation / Q000187:drug effects*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects*; D006561:Herpes Simplex / Q000276:immunology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000502:physiology*; D057131:Immune Evasion; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000276:immunology / Q000502:physiology*; D010641:Phenotype; D012668:Trigeminal Ganglion / Q000276:immunology / Q000821:virology; D017735:Virus Latency / Q000276:immunology
chemical_list: D035683:MicroRNAs; C477253:latency associated transcript, herpes simplex virus-1