The central nervous system is a potential reservoir and possible origin of drug resistance in hepatitis B infection

Lijun Xu; Minghan Zhou; Xiuming Peng; Yufan Xu; Fan Huang; Linyun Wang; Xiaorong Peng; Zongxing Yang; Ran Tao; Guanjing Lang; Qing Cao; Minwei Li; Ying Huang; Biao Zhu; Yan Xu

doi:10.1016/j.jve.2023.100348

The central nervous system is a potential reservoir and possible origin of drug resistance in hepatitis B infection

J Virus Erad. 2023 Sep 11;9(3):100348. doi: 10.1016/j.jve.2023.100348. eCollection 2023 Sep.

Authors

Lijun Xu^{1

2

3}, Minghan Zhou^{1

2

3}, Xiuming Peng⁴, Yufan Xu⁵, Fan Huang⁶, Linyun Wang⁷, Xiaorong Peng^{1

2

3}, Zongxing Yang⁸, Ran Tao^{1

2

3}, Guanjing Lang^{1

2

3}, Qing Cao^{1

2

3}, Minwei Li^{2

3}, Ying Huang¹, Biao Zhu^{1

2

3}, Yan Xu¹

Affiliations

¹ Department of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
² National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
³ The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
⁴ Department of Respiratory Medicine, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
⁵ Department of Pathology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
⁶ Department of Infectious Disease, Jianxin Hospital of Fujian Province, Fuzhou, China.
⁷ College of Medicine, Zhejiang University, Hangzhou, China.
⁸ Department II of Infectious Diseases, Xixi Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Abstract

Background: The significance of hepatitis B virus (HBV) in cerebrospinal fluid (CSF) is unclear.

Methods: Synchronous serum and CSF samples were collected from 13 patients. HBV DNA, full-length genome, quasispecies, phylogenetic tree, compartmentalization and mutation of the reverse transcriptase (RT) region were performed based on PCR and sequencing methods.

Results: HBV DNA was detected in the CSF of 3 antiviral-naïve individuals and 1 individual after successful antiviral therapy. Complete full-length HBV genomes were isolated from the CSF of 5 individuals, including 2 with undetectable serum HBV DNA. Ten individuals exhibited distinct CSF-serum quasispecies, 8 harbored independent CSF-serum genetic compartmentalization and phylogenetic trees, and 5 lamivudine/entecavir-associated resistance mutations only in the CSF. The frequencies of rtL180M and rtM204I/V mutations in both serum and CSF were higher in HIV-HBV-coinfected individuals than in the HBV-monoinfected ones (serum: rtL180M: 3.9% vs. 0, P = 0.004; rtM204I/V: 21.3% vs. 0, P < 0.001; CSF: rtL180M: 7.6% vs. 0, P = 0.026; rtM204I/V 7.6% vs. 1.6%, P = 0.097).

Conclusion: CSF is a potential HBV reservoir, and HBV in CSF harbors distinct evolution and mutation characteristics from those in serum. HIV infection increases the possibility of HBV rtL180M and rtM204I/V mutations in both serum and CSF.

Keywords: Cerebrospinal fluid; HBV; Mutation; Sequence.