Researchers discover new species-specific hepatitis C virus host factor

Researcher Zhong Jin's group at the Shanghai Pasteur Institute of the Chinese Academy of Sciences collaborated with Peking University professor Wei Wensheng's group to publish a research paper titled TRIM26 is a critical host factor for HCV replication and contributes to host tropism on Science Advances.

Hepatitis C virus (HCV) is an RNA virus belonging to the hepatitis C virus genus of the Flaviviridae family.

The direct antiviral drugs (DAA) developed in recent years have improved the efficiency of hepatitis C treatment, but due to the lack of vaccines, the complete elimination of HCV is still challenging.

HCV animal infection model is of great significance to the development of hepatitis C vaccine.
HCV only infects humans and chimpanzees.
Due to ethical issues, the use of chimpanzees as model animals has been banned; transgenic mice expressing HCV receptor molecules can support HCV infection to a limited extent.
Lack of other human host factors, especially host factors for the key steps after the virus enters the cell, the application of this transgenic mouse model in the evaluation of hepatitis C vaccine titer is still limited.

Therefore, the identification of new species-specific HCV host factors is of great significance to the establishment of HCV small animal infection models.

In this study, the researchers found that the E3 ubiquitination ligase TRIM26 is an important host factor for HCV through genome-wide CRISPR/Cas9 screening.

Experimental results show that TRIM26 specifically promotes the replication of the HCV genome, but has no effect on the replication of other viruses belonging to the Flaviviridae family (such as Dengue virus and Zika virus).

Mechanism studies have found that TRIM26 interacts with virus-encoded RNA-dependent RNA replicase NS5B to catalyze the K27-linked ubiquitination modification of lysine at position 51 of NS5B protein, thereby enhancing the NS5B and virus replication complex.
The binding of the protein NS5A ultimately promotes the replication of the HCV genome.

In addition, the study also compared the effects of TRIM26 from different hosts on HCV replication and found that TRIM26 from humans and tree shrews can support virus replication, but TRIM26 from mice cannot support HCV replication.

Sequence analysis found that compared with other species, mouse TRIM26 has a 6-amino acid insertion.
The mouse TRIM26 deleted of the amino acid insertion sequence can partially restore its interaction with the virus NS5B and help virus genome replication.

The study also found that the expression of human TRIM26 in mouse liver cells can significantly enhance the efficiency of HCV infection.

The study discovered a new host factor for HCV and further analyzed the molecular mechanism of HCV replication; it provided new ideas for the establishment of HCV small animal infection models, which is of great significance.

Shanghai Pasteur Institute and Shanghai University of Science and Technology Joint Pei PhD student Liang Yisha, Sun Yat-sen University Zhongshan School of Medicine associate professor Zhang Guigen, Peking University doctoral student Li Qiheng are the co-authors of the paper; Zhong Jin, Wei Wensheng, and Zhang Guigen are the co-corresponding authors of the paper .

Tsinghua University's Ding Qiang group also participated in the research.

The research work is supported by the Chinese Academy of Sciences Strategic Leading Science and Technology Project (Category B), the National Natural Science Foundation of China, and the "Western Light" of the Chinese Academy of Sciences.

The model diagram of TRIM26 helping HCV genome replication.
Source: Shanghai Pasteur Institute, Chinese Academy of Sciences