Herpes Simplex Virus 1 Glycoprotein B and US3 Collaborate To Inhibit CD1d Antigen Presentation and NKT Cell Function

Rao, Venigalla B.; Pham, Hong Thanh; Kulkarni, Arpita; Yang, Yang; Liu, Xueqiao; Knipe, David M.; Cresswell, Peter; Yuan, Weiming

doi:10.1128/jvi.02689-10

Cited by 64 publications

(95 citation statements)

References 76 publications

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“…We and others have shown that herpes simplex virus 1 (HSV-1), the prototype alphaherpesvirus, has evolved to downregulate CD1d expression in antigen-presenting cells and evade NKT cell function (10,13,14). Furthermore, we have demonstrated that the viral protein kinase US3 is a major viral protein that downregulates cell surface expression of CD1d by suppressing its recycling (8).…”

mentioning

confidence: 90%

“…The HSV-1 KOS strain expressing green fluorescent protein (GFP)-fused VP26 protein was generously provided by Prashant Desai (Johns Hopkins University, Baltimore, MD). The HeLa.CD1d cell line has been described previously (8). A rabbit monoclonal antibody (MAb) against KIF3A and a rabbit polyclonal antibody against KIF3B were purchased from Abcam.…”

Section: Methodsmentioning

confidence: 99%

“…As a result of coevolution, most, if not all, herpesviruses have developed intricate mechanisms by which to modulate host immune systems for the benefit of viral survival (6). Because of the importance of NKT cells in antiviral immunity, viruses in all three major herpesvirus families (alpha-, beta-, and gammaherpesviruses) have evolved viral mechanisms to evade CD1d and NKT cell function (7)(8)(9)(10)(11)(12). We and others have shown that herpes simplex virus 1 (HSV-1), the prototype alphaherpesvirus, has evolved to downregulate CD1d expression in antigen-presenting cells and evade NKT cell function (10,13,14).…”

mentioning

confidence: 99%

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Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression

Xiong

Rao

Kim

et al. 2015

J Virol

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Herpes simplex virus 1 (HSV-1) causes one of the most prevalent herpesviral infections in humans and is the leading etiological agent of viral encephalitis and eye infections. Our understanding of how HSV-1 interacts with the host at the cellular and organismal levels is still limited. We and others previously reported that, upon infection, HSV-1 rapidly and efficiently downregulates CD1d cell surface expression and suppresses the function of NKT cells, a group of innate T cells with critical immunoregulatory function. The viral protein kinase US3 plays a major role in this immune evasion mechanism, and its kinase activity is required for this function. In this study, we investigated the cellular substrate(s) phosphorylated by US3 and how it mediates US3 suppression of CD1d recycling. We identified the type II kinesin motor protein KIF3A as a critical kinesin factor in the cell surface expression of CD1d. Interestingly, KIF3A is phosphorylated by US3 both in vitro and in infected cells. Mass spectrometry analysis of purified KIF3A showed that it is phosphorylated predominantly at serine 687 by US3. Ablation of this phosphorylation abolished US3-mediated downregulation of CD1d expression, suggesting that phosphorylation of KIF3A is the primary mechanism of HSV-1 suppression of CD1d expression by US3 protein. Understanding of the precise mechanism of viral modulation of CD1d expression will help to develop more efficient vaccines in the future to boost host NKT cell-mediated immune responses against herpesviruses. IMPORTANCEHerpes simplex virus 1 (HSV-1) is among the most common human pathogens. Little is known regarding the exact mechanism by which this virus evades the human immune system, particularly the innate immune system. We previously reported that HSV-1 employs its protein kinase US3 to modulate the expression of the key antigen-presenting molecule CD1d to evade the antiviral function of NKT cells. Here we identified the key cellular motor protein KIF3A as a cellular substrate phosphorylated by US3, and this phosphorylation event mediates US3-induced immune evasion.

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confidence: 90%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression

Xiong

Rao

Kim

et al. 2015

J Virol

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“…It has been reported that HSV-1 Us3, the best-studied alphaherpesvirus Us3 homologue, blocked apoptosis (16)(17)(18)(19), promoted vesicle-mediated nucleocytoplasmic transport of nucleocapsids through nuclear membranes (20)(21)(22)(23), promoted gene expression by blocking histone deacetylation (24)(25)(26), controlled infected-cell morphology (15,18,27), modulated host immune systems (28)(29)(30)(31)(32)(33)(34)(35), stimulated mRNA translation by activating mTORC1 (36), regulated intracellular trafficking of the abundant virion component UL47 (37) and the essential envelope glycopro-tein B (gB) (38,39), and upregulated the enzymatic activity of viral dUTPase (vdUTPase) (40). These observations suggested that HSV-1 Us3 is a multifunctional protein that regulates various cellular and viral functions by phosphorylating a number of cellular and viral protein substrates.…”

mentioning

confidence: 99%

Characterization of a Herpes Simplex Virus 1 (HSV-1) Chimera in Which the Us3 Protein Kinase Gene Is Replaced with the HSV-2 Us3 Gene

Shindo

Koyanagi

Sagara

et al. 2016

J Virol

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Us3 protein kinases encoded by herpes simplex virus 1 (HSV-1) and 2 (HSV-2) play important roles in viral replication and pathogenicity. To investigate type-specific differences between HSV-1 Us3 and HSV-2 Us3 in cells infected by viruses with all the same viral gene products except for their Us3 kinases, we constructed and characterized a recombinant HSV-1 in which its Us3 gene was replaced with the HSV-2 Us3 gene. Replacement of HSV-1 Us3 with HSV-2 Us3 had no apparent effect on viral growth in cell cultures or on the range of proteins phosphorylated by Us3. HSV-2 Us3 efficiently compensated for HSV-1 Us3 functions, including blocking apoptosis, controlling infected cell morphology, and downregulating cell surface expression of viral envelope glycoprotein B. In contrast, replacement of HSV-1 Us3 by HSV-2 Us3 changed the phosphorylation status of UL31 and UL34, which are critical viral regulators of nuclear egress. It also caused aberrant localization of these viral proteins and aberrant accumulation of primary enveloped virions in membranous vesicle structures adjacent to the nuclear membrane, and it reduced viral cell-cell spread in cell cultures and pathogenesis in mice. These results clearly demonstrated biological differences between HSV-1 Us3 and HSV-2 Us3, especially in regulation of viral nuclear egress and phosphorylation of viral regulators critical for this process. Our study also suggested that the regulatory role(s) of HSV-1 Us3, which was not carried out by HSV-2 Us3, was important for HSV-1 cell-cell spread and pathogenesis in vivo. IMPORTANCEA previous study comparing the phenotypes of HSV-1 and HSV-2 suggested that the HSV-2 Us3 kinase lacked some of the functions of HSV-1 Us3 kinase. The difference between HSV-1 and HSV-2 Us3 kinases appeared to be due to the fact that some Us3 phosphorylation sites in HSV-1 proteins are not conserved in the corresponding HSV-2 proteins. Therefore, we generated recombinant HSV-1 strains YK781 (Us3-chimera) with HSV-2 Us3 and its repaired virus YK783 (Us3-repair) with HSV-1 Us3, to compare the activities of HSV-1 Us3 and HSV-2 Us3 in cells infected by viruses with the same HSV-1 gene products except for their Us3 kinases. We report here that some processes in viral nuclear egress and pathogenesis in vivo that have been attributed to HSV-1 Us3 could not be carried out by HSV-2 Us3. Therefore, our study clarified the biological differences between HSV-1 Us3 and HSV-2 Us3, which may be relevant to viral pathogenesis in vivo.

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“…Estas células del sistema inmune innato reconocen moléculas lipídicas polares, propias del hospedero, denominadas CD1d, las que poseen similitudes estructurales con moléculas de histocompatibilidad de clase I (MHC-I) 111 (Figura 2, panel derecho). Recientemente se ha demostrado que VHS-1 es capaz de impedir la presentación de CD1d en la superficie de células infectadas, mediante el re-direccionamiento de estas moléculas a compartimentos intracelulares 112,113 . Con ello, el virus es capaz de evadir la presentación del ligando a células NKT evitando así la actividad citotó-xica de estas células.…”

Section: El Virus Herpes Simplex Modula La Actividad De Células Nkt Y Nkunclassified

Evasión de la respuesta inmune por virus herpes simplex

Retamal-Díaz

Suazo

Garrido

et al. 2015

Rev. chil. infectol.

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Herpes Simplex Virus 1 Glycoprotein B and US3 Collaborate To Inhibit CD1d Antigen Presentation and NKT Cell Function

Cited by 64 publications

References 76 publications

Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression

Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression

Characterization of a Herpes Simplex Virus 1 (HSV-1) Chimera in Which the Us3 Protein Kinase Gene Is Replaced with the HSV-2 Us3 Gene

Evasión de la respuesta inmune por virus herpes simplex

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