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2019 Vol.34(1)

Host cell cytoskeletons have been reported to have close contact with viruses during virus entry, intracellular transport, replication, and egress process. In this issue, Yue Zhang et al. provide a brief overview of the function of the most prominent flaviviruses-induced or -hijacked cytoskeletal structures including actin, microtubules and intermediate filaments, mainly focus on infection by dengue virus, Zika virus and West Nile virus. The cover image shows host actin cytoskeleton (green) with decorated myosin molecular motor (red) in human osteosarcoma cells (kindly provided by Prof. Yaming Jiu). See page 30–41 for details.

REVIEW

The Asian Lineage of Zika Virus: Transmission and Evolution in Asia and the Americas

Tao Hu, Juan Li, Michael J. Carr, Sebastián Duchȇne, Weifeng Shi

2019, 34(1): 1 doi: 10.1007/s12250-018-0078-2

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Since first isolation in 1947 from the Zika forest in Uganda, Zika virus (ZIKV) has been principally known as a benign agent associated with sporadic human infections in a restricted number of African countries. However, during 2015–2016, an Asian lineage of ZIKV caused an unprecedentedly large outbreak in the Americas and sizeable numbers of exported cases across the globe. In this review, we critically appraise the recent advances in molecular epidemiological studies of ZIKV performed to date, and we highlight the pivotal role played by genomic surveillance in elucidating the origins, dissemination and evolution of the Asian lineage of ZIKV in Asia and in the Americas.

Recent Progress on Functional Genomics Research of Enterovirus 71

Huiqiang Wang, Yuhuan Li

2019, 34(1): 9 doi: 10.1007/s12250-018-0071-9

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Enterovirus 71 (EV71) is one of the main pathogens that causes hand-foot-and-mouth disease (HFMD). HFMD caused by EV71 infection is mostly self-limited; however, some infections can cause severe neurological diseases, such as aseptic meningitis, brain stem encephalitis, and even death. There are still no effective clinical drugs used for the prevention and treatment of HFMD. Studying EV71 protein function is essential for elucidating the EV71 replication process and developing anti-EV71 drugs and vaccines. In this review, we summarized the recent progress in the studies of EV71 noncoding regions (5' UTR and 3' UTR) and all structural and nonstructural proteins, especially the key motifs involving in viral infection, replication, and immune regulation. This review will promote our understanding of EV71 virus replication and pathogenesis, and will facilitate the development of novel drugs or vaccines to treat EV71.

Regulation of Virus Replication and T Cell Homeostasis by N6-Methyladenosine

Jing Yang, Hong Wang, Wenyan Zhang

2019, 34(1): 22 doi: 10.1007/s12250-018-0075-5

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RNA modifications are abundant in eukaryotes, bacteria, and archaea. N6-methyladenosine (m6A), a type of RNA modification mainly found in messenger RNA (mRNA), has significant effects on the metabolism and function of mRNAs. This modification is governed by three types of proteins, namely methyltransferases as 'writers', demethylases as 'erasers', and specific m6A-binding proteins (YTHDF1-3) as 'readers'. Further, it is important for the regulation of cell fate and has a critical function in many biological processes including virus replication, stem cell differentiation, and cancer development, and exerts its effect by controlling gene expression. Herein, we summarize recent advances in research on m6A in virus replication and T cell regulation, which is a rapidly emerging field that will facilitate the development of antiviral therapies and the study of innate immunity.

The Role of Host Cytoskeleton in Flavivirus Infection

Yue Zhang, Wei Gao, Jian Li, Weihua Wu, Yaming Jiu

2019, 34(1): 30 doi: 10.1007/s12250-019-00086-4

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The family of flaviviruses is one of the most medically important groups of emerging arthropod-borne viruses. Host cell cytoskeletons have been reported to have close contact with flaviviruses during virus entry, intracellular transport, replication, and egress process, although many detailed mechanisms are still unclear. This article provides a brief overview of the function of the most prominent flaviviruses-induced or -hijacked cytoskeletal structures including actin, microtubules and intermediate filaments, mainly focus on infection by dengue virus, Zika virus and West Nile virus. We suggest that virus interaction with host cytoskeleton to be an interesting area of future research.
Research Article

The Variability of Amino Acid Sequences in Hepatitis B Virus

Jianhao Cao, Shuhong Luo, Yuanyan Xiong

2019, 34(1): 42 doi: 10.1007/s12250-018-0070-x

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Hepatitis B virus (HBV) is an important human pathogen belonging to the Hepadnaviridae family, Orthohepadnavirus genus. Over 240 million people are infected with HBV worldwide. The reverse transcription during its genome replication leads to low fidelity DNA synthesis, which is the source of variability in the viral proteins. To investigate the variability quantitatively, we retrieved amino acid sequences of 5, 167 records of all available HBV genotypes (A–J) from the Genbank database. The amino acid sequences encoded by the open reading frames (ORF) S/C/P/X in the HBV genome were extracted and subjected to alignment. We analyzed the variability of the lengths and the sequences of proteins as well as the frequencies of amino acids. It comprehensively characterized the variability and conservation of HBV proteins at the level of amino acids. Especially for the structural proteins, hepatitis B surface antigens (HBsAg), there are potential sites critical for virus assembly and immune recognition. Interestingly, the preS1 domains in HBsAg were variable at some positions of amino acid residues, which provides a potential mechanism of immune-escape for HBV, while the preS2 and S domains were conserved in the lengths of protein sequences. In the S domain, the cysteine residues and the secondary structures of the alpha-helix and beta-sheet were likely critical for the stable folding of all HBsAg components. Also, the preC domain and C-terminal domain of the core protein are highly conserved. However, the polymerases (HBpol) and the HBx were highly variable at the amino acid level. Our research provides a basis for understanding the conserved and important domains of HBV viral proteins, which could be potential targets for anti-virus therapy.

Molecular Epidemiology of Echovirus 18 Circulating in Mainland China from 2015 to 2016

Xiangpeng Chen, Tianjiao Ji, Jiayun Guo, Wei Wang, Wenbo Xu, Zhengde Xie

2019, 34(1): 50 doi: 10.1007/s12250-018-0080-8

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Echovirus 18 (E18), a serotype of Enterovirus B (EV-B) species, is an important pathogen in aseptic meningitis. E18 had rarely been detected in mainland China, but became the predominant pathogen associated with viral encephalitis (VE) and meningitis in Hebei province for the first time in 2015. To investigate the molecular epidemiology and genetic characteristics of E18 in mainland China, sixteen E18 strains from patient throat swabs with hand, foot, and mouth disease (HFMD) in six provinces in China collected between 2015 and 2016, and four E18 strains isolated from 18 patient cerebrospinal fluid specimens with VE in Hebei Province in 2015 were obtained and sequenced. Combined with the sequences from the GenBank database, we performed an extensive genetic analysis. Phylogenetic analysis of VP1 gene sequences revealed that all E18 strains from mainland China after 2015 belonged to subgenotype C2. There were no obvious specific differences in phylogenetic and variation analyses of E18 genome sequences between HFMD and VE/meningitis strains. Potential multiple recombination may have occurred in the 50-untranslated region and in the P2 and P3 nonstructural protein-encoding regions of E18 strains from China. The current E18 strains were potential multiplerecombinant viruses. Overall, these findings supported that E18 caused HFMD, VE, and meningitis, although there were no significant associations between clinical features and viral genomic characteristics.

Exosomes Released from Rabies Virus-Infected Cells May be Involved in the Infection Process

Jingyu Wang, Fan Wu, Chuntian Liu, Wenwen Dai, Yawei Teng, Weiheng Su, Wei Kong, Feng Gao, Linjun Cai, Ali Hou, Chunlai Jiang

2019, 34(1): 59 doi: 10.1007/s12250-019-00087-3

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Exosomes are cell-derived vesicles that are secreted by many eukaryotic cells. It has recently attracted attention as vehicles of intercellular communication. Virus-infected cells release exosomes, which contain viral proteins, RNA, and pathogenic molecules. However, the role of exosomes in virus infection process remains unclear and needs to be further investigated. In this study, we aimed to evaluate the effects of exosomes on rabies virus infection. OptiPrepTM density gradient centrifugation was used to isolate exosomes from rabies virus-infected cell culture supernatants. A rabies virus G protein enzyme-linked immunosorbent assay and acetylcholinesterase activity assays were performed to verify the centrifugation fractions. Exosomes were then characterized using transmission electron microscopy and Western blotting. Our results showed that rabies virus infection increased the release of exosomes. Treatment with GW4869 and si-Rab27a, two exosomal secretion inhibitors, inhibited exosome release. Furthermore, the inhibitors reduced the levels of extracellular and intracellular viral RNA. These data indicated that exosomes may participate in the viral infection process. Moreover, our results establish a basis for future research into the roles of exosomes in rabies virus infection and as potential targets for developing new antiviral strategies.

Polypyrimidine Tract-Binding Protein Regulates Enterovirus 71 Translation Through Interaction with the Internal Ribosomal Entry Site

Juemin Xi, Fei Ye, Guanzhou Wang, Wei Han, Zhizhong Wei, Bin Yin, Jiangang Yuan, Boqin Qiang, Xiaozhong Peng

2019, 34(1): 66 doi: 10.1007/s12250-019-00089-1

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Enterovirus 71 (EV71), a major causative agent of hand, foot, and mouth disease, has caused periodic infection outbreaks in children in the Asia–Pacific region. In order to describe the largely unknown life cycle of EV71, the molecular basis of its virus-host interactions must first be determined. The 50 untranslated region of EV71 contains a cloverleaf-like structure and internal ribosomal entry site (IRES), which play an important role in transcription and translation of viral protein. We found that polypyrimidine tract-binding protein 1 (PTB) bound to the IRES of EV71. RNA recognition motifs 1 and 2 of PTB were responsible for its binding to the EV71 IRES. Moreover, PTB protein was shuttled from nucleus to cytoplasm after EV71 infection. Additionally, IRES activity and viral protein production were inhibited by PTB knockdown. These results suggest that PTB interacts with the EV71 IRES, and positively regulates viral protein translation.

Oxymatrine Inhibits Bocavirus MVC Replication, Reduces Viral Gene Expression and Decreases Apoptosis Induced by Viral Infection

Yanqin Ding, Na Li, Jinhan Sun, Linran Zhang, Jianhui Guo, Xueqi Hao, Yuning Sun

2019, 34(1): 78 doi: 10.1007/s12250-019-00088-2

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Oxymatrine (OMT), as the main active component of Sophoraflavescens, exhibits a variety of pharmacological properties, including anti-oxidative, anti-inflammatory, anti-tumor, and anti-viral activities, and currently is extensively employed to treat viral hepatitis; however, its effects on parvovirus infection have yet to be reported. In the present study, we investigated the effects of OMT on cell viability, virus DNA replication, viral gene expression, cell cycle, and apoptosis in Walter Reed canine cells/3873D infected with minute virus of canines (MVC). OMT, at concentrations below 4 mmol/L(no cellular toxicity), was found to inhibit MVC DNA replication and reduce viral gene expression at both mRNA and protein levels, which was associated with the inhibition of cell cycle S-phase arrest in early-stage of MVC infection. Furthermore, OMT significantly increased cell viability, decreased MVC-infected cell apoptosis, and reduced the expression of activated caspase 3. Our results suggest that OMT has potential application in combating parvovirus infection.

Electroporation-Mediated Immunization of a Candidate DNA Vaccine Expressing Dengue Virus Serotype 4 prM-E Antigen Confers Long-Term Protection in Mice

Ziyang Sheng, Hui Chen, Kaihao Feng, Na Gao, Ran Wang, Peigang Wang, Dongying Fan, Jing An

2019, 34(1): 88 doi: 10.1007/s12250-019-00090-8

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Dengue fever, caused by dengue viruses (DENVs), is a widespread mosquito-borne zoonotic disease; however, there is no available anti-dengue vaccine for worldwide use. In the current study, a DNA vaccine candidate (pV-D4ME) expressing prM-E protein of DENV serotype 4 (DENV-4) was constructed, and its immunogenicity and protection were evaluated in immunocompetent BALB/c mice. The pV-D4ME candidate vaccine induced effective humoral and cellular immunity of mice against DENV-4 in vivo when administered both at 50 μg and 5 μg through electroporation. Two weeks after receiving three immunizations, both doses of pV-D4ME DNA were shown to confer effective protection against lethal DENV-4 challenge. Notably, at 6 months after the three immunizations, 50 μg, but not 5 μg, of pV-D4ME could provide stable protection (100% survival rate) against DENV-4 lethal challenge without any obvious clinical signs. These results suggest that immunization with 50 μg pV-D4ME through electroporation could confer effective and long-term protection against DENV-4, offering a promising approach for development of a novel DNA vaccine against DENVs.
LETTER

Low Pathogenic Avian Influenza A (H5N7) Virus Isolated from a Domestic Duck in Dongting Lake Wetland of China, 2016

Liping Ma, Haizhou Liu, Runkun Wang, Tao Jin, Di Liu, George Fu Gao, Quanjiao Chen

2019, 34(1): 97 doi: 10.1007/s12250-018-0081-7

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The avian influenza virus (AIV) H5N7 was first isolated from wild birds in North America in 2001 (Spackman et al., 2007), and information on only 25 strains of this virus has been deposited in the Global Initiative on Sharing All Influenza Data (GISAID-http://platform.gisaid.org/epi3/frontend#493de3) database until October 30, 2018. Twenty viruses were identified in the United States from 2001 to 2017, three viruses in Denmark in 2003, and two viruses in Mongolia in 2014 (GISAID-http://platform.gisaid.org/epi3/frontend#493de3). All these H5N7 viruses were low pathogenicity and were discovered in wild migratory birds.

Pathogenic Characterization and Full Length Genome Sequence of a Reassortant Infectious Bursal Disease Virus Newly Isolated in Pakistan

Altaf Hussain, Tiantian Wu, Hui Li, Linjin Fan, Kai Li, Li Gao, Yongqiang Wang, Yulong Gao, Changjun Liu, Hongyu Cui, Qing Pan, Yanping Zhang, Asim Aslam, Khan Muti-Ur-Rehman, Muhammad Munir, Salman Latif Butt, Xiaomei Wang, Xiaole Qi

2019, 34(1): 102 doi: 10.1007/s12250-019-00082-8

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Infectious bursal disease (IBD), caused by IBD virus (IBDV), is one of the most devastating diseases of the poultry. Despite the use of mass- and intense-vaccination regimens, the disease continues to sustain in many countries around the globe including Pakistan. This highlights the need to ascertain the characterization of field circulating strains at resolution that provides evidences of vaccine failures. In this study, a naturally occurring reassortant IBDV (referred as PK2) was identified and for the first time the full-genomic and pathogenic characterization of Pakistan strain was revealed. Genome analysis showed that the segment A of PK2 was derived from a very virulent IBDV (vvIBDV) whereas the segment B was acquired from another unique ancestor. Furthermore, infection of SPF chickens with PK2 revealed the potential of the virus in causing infection and inducing pathologies. Taken together, the present study provides useful data for further understanding of the popular and evolution of IBDV, which will helpfully support a better prevention and control of the disease in Pakistan.

A Vesicular Stomatitis Virus-Based Vaccine Carrying Zika Virus Capsid Protein Protects Mice from Viral Infection

Xiaodan Shi, Jingping Hu, Jing Guo, Chuanjian Wu, Sidong Xiong, Chunsheng Dong

2019, 34(1): 106 doi: 10.1007/s12250-019-00083-7

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ZIKV infection can cause other severe neurological disorders, such as Guillain-Barré syndrome. Currently, more than 70 countries have reported Zika virus (ZIKV) infections, making it a global public health issue. However, there is no clinically approved vaccine available. Flaviviruses often show antigenic cross-reactivity, which can be beneficial and result in cross-protection. However, humoral cross-reactivity can also exacerbate disease via antibody-dependent enhancement (ADE). The prM-E proteins have been the primary targets of most ZIKV vaccine candidates. Therefore, to increase safety, it is necessary to investigate the use of protective ZIKV antigen for vaccine development as compared with prM-E or E protein. The capsid protein plays a crucial role in Flaviviridae biology, with a report indicating that a dengue virus vaccine engineered with a capsid protein alone produced neutralizing-antibody independent immunity and significantly reduced viral loads in the brains of challenged monkeys. In the present study, a recombinant vesicular stomatitis virus (VSV)-based vaccine carrying the ZIKV capsid protein (VSV-Capsid) was generated. VSV-capsid vaccination induced strong humoral immune response as well as cellular immune response compared with E protein based vaccine (VSV-E260-425). More importantly, the protective role was found in mice with VSV-capsid vaccination upon ZIKV infection. The viral RNA is significantly reduced in spinal cord, brain and testis of these immunized mice. Our findings demonstrated that the ZIKV capsid protein was an effective antigen in VSV vector-based delivery for ZIKV vaccine design.

Genetic Analysis of an Emerging GII.P2–GII.2 Norovirus Associated with a 2016 Outbreak of Acute Gastroenteritis in China

Yuanyun Ao, Xiaolu Xie, Xiaogen Dong, Miao Jin, Zhaojun Duan

2019, 34(1): 111 doi: 10.1007/s12250-019-00084-6

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 In the 2016–2017 winter season, a GII.P16-GII.2 norovirus that had previously been rarely detected was responsible for a majority of the outbreaks of gastroenteritis in China and other countries. Another GII.2 virus, GII.P2-GII.2, had been rarely reported as a cause of gastroenteritis outbreaks since 2010. In this study, an emerging GII.P2-GII.2 variant was identified to be involved in an outbreak in the Fengtai District, Beijing, China in December 2016. Sequence and phylogenetic analyses indicated that this GII.2 strain is a novel recombinant virus that evolved in the 2011–2012 season from the 2011–2012 GII.P16-GII.2 and 2011 GII.P2-GII.2 strains. Phylogenetic analyses indicated that this GII.2 strain appears to have been introduced to China from Russia, where it was first detected as being involved in sporadic gastroenteritis in July 2016. Sequence analyses revealed that no significant mutation both in the VP1 and polymerase proteins was observed in this virus. Continuous surveillance of the epidemiology of this norovirus is necessary to further understand its evolution and significance in public health.
CORRECTION

Correction to:Genetic Evidence of Middle East Respiratory Syndrome Coronavirus (MERS-Cov) and Widespread Seroprevalence among Camels in Kenya

Sheila Ommeh, Wei Zhang, Ali Zohaib, Jing Chen, Huajun Zhang, Ben Hu, Xing-Yi Ge, Xing-Lou Yang, Moses Masika, Vincent Obanda, Yun Luo, Shan Li, Cecilia Waruhiu, Bei Li, Yan Zhu, Desterio Ouma, Vincent Odendo, Lin-Fa Wang, Danielle E. Anderson, Jacqueline Lichoti, Erick Mungube, Francis Gakuya, Peng Zhou, Kisa-Juma Ngeiywa, Bing Yan, Bernard Agwanda, Zheng-Li Shi

2019, 34(1): 115 doi: 10.1007/s12250-019-00092-6

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