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

Chronic hepatitis B (CHB) infection is rarely eradicated by current antiviral nucleos(t)ide analogues. We found that [alpha]2,6-biantennary sialoglycans of HBV surface antigen (HBsAg) bound human SIGLEC-3 (CD33) by IP and ELISA, and the binding affinity between SIGLEC-3 and [alpha]2,6-biantennary si...

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Bibliographic Details
Published in:The Journal of clinical investigation 2021-06, Vol.131 (11)
Main Authors: Tsai, Tsung-Yu, Huang, Ming-Ting, Sung, Pei-Shan, Peng, Cheng-Yuan, Tao, Mi-Hua, Yang, Hwai-I, Chang, Wei-Chiao, Yang, An-Suei, Yu, Chung-Ming, Lin, Ya-Ping, Bau, Ching-Yu, Huang, Chih-Jen, Pan, Mei-Hung, Wu, Chung-Yi, Hsiao, Chwan-Deng, Yeh, Yi-Hung, Duan, Shiteng, Paulson, James C, Hsieh, Shie-Liang
Format: Article
Language:English
Subjects:
Complications and side effects
Development and progression
Health aspects
Hepatitis associated antigen
Hepatitis B
Hepatoma
Lectins
Membrane proteins
Physiological aspects
Prevention
Risk factors
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Summary:Chronic hepatitis B (CHB) infection is rarely eradicated by current antiviral nucleos(t)ide analogues. We found that [alpha]2,6-biantennary sialoglycans of HBV surface antigen (HBsAg) bound human SIGLEC-3 (CD33) by IP and ELISA, and the binding affinity between SIGLEC-3 and [alpha]2,6-biantennary sialoglycans was determined by biolayer interferometry (equilibrium dissociation constant [KD]: 1.95 * [10.sup.-10] [+ or -] 0.21 * [10.sup.-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 [alpha]2,6-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.sup.+] 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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI141965