TY - JOUR

T1 - Epstein-Barr Virus-Encoded BILF1 Orthologues From Porcine Lymphotropic Herpesviruses Display Common Molecular Functionality

AU - Mavri, Maša

AU - Kubale, Valentina

AU - Depledge, Daniel P.

AU - Zuo, Jianmin

AU - Huang, Christene A.

AU - Breuer, Judith

AU - Vrecl, Milka

AU - Jarvis, Michael A.

AU - Jovičić, Eva Jarc

AU - Petan, Toni

AU - Ehlers, Bernhard

AU - Rosenkilde, Mette M.

AU - Spiess, Katja

N1 - Publisher Copyright: Copyright © 2022 Mavri, Kubale, Depledge, Zuo, Huang, Breuer, Vrecl, Jarvis, Jovičić, Petan, Ehlers, Rosenkilde and Spiess.

PY - 2022

Y1 - 2022

N2 - Infection of immunosuppressed transplant patients with the human γ-herpesvirus Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disease (PTLD), an often fatal complication. Immunosuppressed miniature pigs infected with γ-herpesvirus porcine lymphotropic herpesvirus 1 (PLHV1) develop a similar disease, identifying pigs as a potential preclinical model for PTLD in humans. BILF1 is a G protein-coupled receptor (GPCR) encoded by EBV with constitutive activity linked to tumorigenesis and immunoevasive function downregulating MHC-I. In the present study, we compared BILF1-orthologues encoded by the three known PLHVs (PLHV1-3) with EBV-BILF1 to determine pharmacological suitability of BILF1 orthologues as model system to study EBV-BILF1 druggability. Cell surface localization, constitutive internalization, and MHC-I downregulation as well as membrane proximal constitutive Gαi signaling patterns were conserved across all BILFs. Only subtle differences between the individual BILFs were observed in downstream transcription factor activation. Using Illumina sequencing, PLHV1 was observed in lymphatic tissue from PTLD-diseased, but not non-diseased pigs. Importantly, these tissues showed enhanced expression of PLHV1-BILF1 supporting its involvement in PTLD infection.

AB - Infection of immunosuppressed transplant patients with the human γ-herpesvirus Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disease (PTLD), an often fatal complication. Immunosuppressed miniature pigs infected with γ-herpesvirus porcine lymphotropic herpesvirus 1 (PLHV1) develop a similar disease, identifying pigs as a potential preclinical model for PTLD in humans. BILF1 is a G protein-coupled receptor (GPCR) encoded by EBV with constitutive activity linked to tumorigenesis and immunoevasive function downregulating MHC-I. In the present study, we compared BILF1-orthologues encoded by the three known PLHVs (PLHV1-3) with EBV-BILF1 to determine pharmacological suitability of BILF1 orthologues as model system to study EBV-BILF1 druggability. Cell surface localization, constitutive internalization, and MHC-I downregulation as well as membrane proximal constitutive Gαi signaling patterns were conserved across all BILFs. Only subtle differences between the individual BILFs were observed in downstream transcription factor activation. Using Illumina sequencing, PLHV1 was observed in lymphatic tissue from PTLD-diseased, but not non-diseased pigs. Importantly, these tissues showed enhanced expression of PLHV1-BILF1 supporting its involvement in PTLD infection.

KW - BILF1

KW - drug target

KW - Epstein-Barr virus

KW - G protein signaling

KW - in-vivo model

KW - MHC class I

KW - porcine lymphotropic herpesviruses (PLHV)

KW - post-transplant lymphoproliferative disease

UR - http://www.scopus.com/inward/record.url?scp=85132880308&partnerID=8YFLogxK

U2 - 10.3389/fendo.2022.862940

DO - 10.3389/fendo.2022.862940

M3 - Journal article

C2 - 35721730

AN - SCOPUS:85132880308

VL - 13

JO - Frontiers in Endocrinology

JF - Frontiers in Endocrinology

SN - 1664-2392

M1 - 862940

ER -