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. 2014 Mar;60(3):515-22.
doi: 10.1016/j.jhep.2013.11.004. Epub 2013 Nov 13.

N-glycosylation mutations within hepatitis B virus surface major hydrophilic region contribute mostly to immune escape

De-Min Yu  1 , Xin-Hua Li  2 , Vannary Mom  3 , Zhong-Hua Lu  4 , Xiang-Wei Liao  1 , Yue Han  1 , Christian Pichoud  3 , Qi-Ming Gong  1 , Dong-Hua Zhang  1 , Yan Zhang  5 , Paul Deny  6 , Fabien Zoulim  7 , Xin-Xin Zhang  8
Affiliations

N-glycosylation mutations within hepatitis B virus surface major hydrophilic region contribute mostly to immune escape

De-Min Yu et al. J Hepatol. 2014 Mar.

Abstract

Background & aims: HBV immune escape represents a challenge to prevention, diagnosis, and treatment of hepatitis B. Here, we analyzed the molecular and clinical characteristics of HBV immune escape mutants in a Chinese cohort of chronically infected patients.

Methods: Two hundred sixteen patients with HBsAg and anti-HBs were studied, with one hundred eighty-two HBV carriers without anti-HBs as a control group. Recombinant HBsAg bearing the most frequent N-glycosylation mutations were expressed in CHO and HuH7 cells. After confirming N-glycosylation at the most frequent sites (129 and 131), together with inserted mutations, functional analysis were performed to study antigenicity and secretion capacity.

Results: One hundred twenty-three patients had the wild-type HBs gene sequence, 93 patients (43%) had mutants in the major hydrophilic region (MHR), and 47 of the 93 patients had additional N-glycosylation mutations, which were transmitted horizontally to at least 2 patients, one of whom was efficiently vaccinated. The frequency of N-glycosylation mutation in the case group was much higher than that of the control group (47/216 vs. 1/182). Compared with wild-type HBsAg, HBsAg mutants reacted weakly with anti-HBs using a chemiluminescent microparticle enzyme immunoassay. Native gel analysis of secreted virion in supernatants of transfected HuH7 cells indicated that mutants had better virion enveloping and secretion capacity than wild-type HBV.

Conclusions: Our results suggest that specific HBsAg MHR N-glycosylation mutations are implicated in HBV immune escape in a high endemic area.

Keywords: AHB; ALT; Acute Hepatitis B; CHB; CMIA; Chronic Hepatitis B; HBV; HBsAg; HCC; Immune escape; LC; MHR; Major hydrophilic region; Mutation; N-glycosylation; PCR; Polymerase chain reaction; aa; amino acid; anti-HBs; anti-HBs antibodies; aspartate aminotransferase; chemiluminescent microparticle enzyme immunoassay; hepatitis B virus; hepatitis B virus surface antigen; hepatocellular carcinoma; liver cirrhosis; major hydrophilic region; rHBsAg; recombinant hepatitis B virus surface antigen.

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