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Pathogenesis and Immunity

Restoring Herpesvirus Entry Mediator (HVEM) Immune Function in HVEM−/− Mice Rescues Herpes Simplex Virus 1 Latency and Reactivation Independently of Binding to Glycoprotein D

Kati Tormanen, Shaohui Wang, Ujjaldeep Jaggi, Homayon Ghiasi
Jae U. Jung, Editor
Kati Tormanen
aCenter for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los Angeles, California, USA
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Shaohui Wang
aCenter for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los Angeles, California, USA
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Ujjaldeep Jaggi
aCenter for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los Angeles, California, USA
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Homayon Ghiasi
aCenter for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los Angeles, California, USA
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  • ORCID record for Homayon Ghiasi
Jae U. Jung
University of Southern California
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DOI: 10.1128/JVI.00700-20
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ABSTRACT

The immune modulatory protein herpes virus entry mediator (HVEM) is one of several cellular receptors used by herpes simplex virus 1 (HSV-1) for cell entry. HVEM binds to HSV-1 glycoprotein D (gD) but is not necessary for HSV-1 replication in vitro or in vivo. Previously, we showed that although HSV-1 replication was similar in wild-type (WT) control and HVEM−/− mice, HSV-1 does not establish latency or reactivate effectively in mice lacking HVEM, suggesting that HVEM is important for these functions. It is not known whether HVEM immunomodulatory functions contribute to latency and reactivation or whether its binding to gD is necessary. We used HVEM−/− mice to establish three transgenic mouse lines that express either human WT HVEM or human or mouse HVEM with a point mutation that ablates its ability to bind to gD. Here, we show that HVEM immune function, not its ability to bind gD, is required for WT levels of latency and reactivation. We further show that HVEM binding to gD does not affect expression of the HVEM ligands BTLA, CD160, or LIGHT. Interestingly, our results suggest that binding of HVEM to gD may contribute to efficient upregulation of CD8α but not PD1, TIM-3, CTLA4, or interleukin 2 (IL-2). Together, our results establish that HVEM immune function, not binding to gD, mediates establishment of latency and reactivation.

IMPORTANCE HSV-1 is a common cause of ocular infections worldwide and a significant cause of preventable blindness. Corneal scarring and blindness are consequences of the immune response induced by repeated reactivation events. Therefore, HSV-1 therapeutic approaches should focus on preventing latency and reactivation. Our data suggest that the immune function of HVEM plays an important role in the HSV-1 latency and reactivation cycle that is independent of HVEM binding to gD.

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Restoring Herpesvirus Entry Mediator (HVEM) Immune Function in HVEM−/− Mice Rescues Herpes Simplex Virus 1 Latency and Reactivation Independently of Binding to Glycoprotein D
Kati Tormanen, Shaohui Wang, Ujjaldeep Jaggi, Homayon Ghiasi
Journal of Virology Jul 2020, 94 (16) e00700-20; DOI: 10.1128/JVI.00700-20

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Restoring Herpesvirus Entry Mediator (HVEM) Immune Function in HVEM−/− Mice Rescues Herpes Simplex Virus 1 Latency and Reactivation Independently of Binding to Glycoprotein D
Kati Tormanen, Shaohui Wang, Ujjaldeep Jaggi, Homayon Ghiasi
Journal of Virology Jul 2020, 94 (16) e00700-20; DOI: 10.1128/JVI.00700-20
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KEYWORDS

cornea
virus replication
transgenic
exhaustion
eye disease
herpes simplex virus 1
HSV-1
herpesvirus entry mediator
HVEM
latency
ocular infection
reactivation

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