SIGLEC-3 (CD33) serves as an immune checkpoint receptor for HBV infection

Tsung Yu Tsai, Ming Ting Huang, Pei Shan Sung, Cheng Yuan Peng, Mi Hua Tao, Hwai I. Yang, Wei Chiao Chang, An Suei Yang, Chung Ming Yu, Ya Ping Lin, Ching Yu Bau, Chih Jen Huang, Mei Hung Pan, Chung Yi Wu, Chwan Deng Hsiao, Yi Hung Yeh, Shiteng Duan, James C. Paulson, Shie Liang Hsieh

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Chronic hepatitis B (CHB) infection is rarely eradicated by current antiviral nucleos(t)ide analogues. We found that α2,6-biantennary sialoglycans of HBV surface antigen (HBsAg) bound human SIGLEC-3 (CD33) by IP and ELISA, and the binding affinity between SIGLEC-3 and α2,6-biantennary sialoglycans was determined by biolayer interferometry (equilibrium dissociation constant [KD]: 1.95 × 10–10 ± 0.21 × 10–10 M). Moreover, HBV activated SIGLEC-3 on myeloid cells and induced immunosuppression by stimulating immunoreceptor tyrosine-based inhibitory motif phosphorylation and SHP-1/-2 recruitment via α2,6-biantennary sialoglycans on HBsAg. An antagonistic anti–SIGLEC-3 mAb reversed this effect and enhanced cytokine production in response to TLR-7 agonist GS-9620 in PBMCs from CHB patients. Moreover, anti–SIGLEC-3 mAb alone was able to upregulate the expression of molecules involved in antigen presentation, such as CD80, CD86, CD40, MHC-I, MHC-II, and PD-L1 in CD14+ cells. Furthermore, SIGLEC-3 SNP rs12459419 C, which expressed a higher amount of SIGLEC-3, was associated with increased risk of hepatocellular carcinoma (HCC) in CHB patients (HR: 1.256, 95% CI: 1.027–1.535, P = 0.0266). Thus, blockade of SIGLEC-3 is a promising strategy to reactivate host immunity to HBV and lower the incidence of HCC in the CHB patient population.

Original languageEnglish
Article numbere141965
JournalJournal of Clinical Investigation
Volume131
Issue number11
DOIs
Publication statusPublished - Jun 2021

ASJC Scopus subject areas

  • Medicine(all)

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