The gamma 1 34.5 protein of herpes simplex virus 1 is required to interfere with dendritic cell maturation during productive infection.
The gamma(1)34.5 protein of herpes simplex virus 1 is an essential factor for viral virulence. In infected cells, this viral protein prevents the translation arrest mediated by double-stranded RNA-dependent protein kinase R. Additionally, it associates with and inhibits TANK-binding kinase 1, an essential component of Toll-like receptor-dependent and -independent pathways that activate interferon regulatory factor 3 and cytokine expression. Here, we show that gamma(1)34.5 is required to block the maturation of conventional dendritic cells (DCs) that initiate adaptive immune responses. Unlike wild-type virus, the gamma(1)34.5 null mutant stimulates the expression of CD86, major histocompatibility complex class II (MHC-II), and cytokines such as alpha/beta interferon in immature DCs. Viral replication in DCs inversely correlates with interferon production. These phenotypes are also mirrored in a mouse ocular infection model. Further, DCs infected with the gamma(1)34.5 null mutant effectively activate naive T cells whereas DCs infected with wild-type virus fail to do so. Type I interferon-neutralizing antibodies partially reverse virus-induced upregulation of CD86 and MHC-II, suggesting that gamma(1)34.5 acts through interferon-dependent and -independent mechanisms. These data indicate that gamma(1)34.5 is involved in the impairment of innate immunity by inhibiting both type I interferon production and DC maturation, leading to defective T-cell activation.
Jin
Huali
H
Department of Microbiology and Immunology, College of Medicine, The University of Illinois at Chicago, 835 South Wolcott Ave., Chicago, IL 60612, USA.
Ma
Yijie
Y
Prabhakar
Bellur S
BS
Feng
Zongdi
Z
Valyi-Nagy
Tibor
T
Yan
Zhipeng
Z
Verpooten
Dustin
D
Zhang
Cuizhu
C
Cao
Youjia
Y
He
Bin
B
D000818:Animals; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism; D002522:Chlorocebus aethiops; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D004195:Disease Models, Animal; D005123:Eye / Q000276:immunology / Q000821:virology; D005802:Genes, MHC Class II; D006561:Herpes Simplex / Q000276:immunology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014709:Vero Cells; D014764:Viral Proteins / Q000276:immunology* / Q000378:metabolism
D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D007370:Interferon Type I; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1