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2018 Vol.33(4)

Stress granules (SGs) are intracellular granules formed when cellular translation is blocked. Viral infections can induce the formation of SGs, which in turn promote or inhibit viral infection. In this issue, Xia Zhai et al. investigated the effect of coxsackievirus B type 3 (CVB3) infection on SG formation, and found that CVB3 could induce SG formation in the early phase of infection, while SGs could in turn restrict the biosynthesis of CVB3 in host cells. The cover image shows the formation of stress granules (green dots) in HeLa cells infected with CVB3 (red) for 6 h (kindly provided by Prof. Zhaohua Zhong). See page 314–322 for details.

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Research Article

Hepatitis C in Laos: A 7-Year Retrospective Study on 1765 Patients

Phimpha Paboriboune, Thomas Vial, Philavanh Sitbounlang, Stéphane Bertani, Christian Trépo, Paul Dény, Francois-Xavier Babin, Nicolas Steenkeste, Pascal Pineau, Eric Deharo

2018, 33(4): 295 doi: 10.1007/s12250-018-0039-9

Received: 20 April 2018 Accepted: 25 May 2018 Published: 13 June 2018
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Hepatitis C (HCV) is a global health concern, notably in Southeast Asia, and in Laos the presentation of the disease is poorly known. Our objective was thus to describe a comprehensive HCV infection pattern in order to guide national health policies. A study on a group of 1,765 patients formerly diagnosed by rapid test in health centres was conducted at the Centre of Infectiology Lao Christophe Merieux in Vientiane. The demographic information of patients, their infection status (viral load: VL), liver function (aminotransferases) and treatments were analysed. Results showed that gender distribution of infected people was balanced; with median ages of 53.8 for men and 51.6 years for women (13–86 years). The majority of patients (72%) were confirmed positive (VL > 50 IU/mL) and 28 % of them had high VL (> 6log10). About 23% of patients had level of aminotransferases indicative of liver damage (> 40 IU/mL); but less than 20 % of patients received treatment. Patients rarely received a second sampling or medical imaging. The survey also showed that cycloferon, pegylated interferon and ribavirin were the drugs prescribed preferentially by the medical staff, without following any international recommendations schemes. In conclusion, we recommend that a population screening policy and better management of patients should be urgently implemented in the country, respecting official guidelines. However, the cost of biological analysis and treatment are significant barriers that must be removed. Public health resolutions should be immediately enforced in the perspective of meeting the WHO HCV elimination deadline by 2030.

Molecular-Genetic Characterization of Human Rotavirus A Strains Circulating in Moscow, Russia (2009–2014)

Victoria Kiseleva, Evgeny Faizuloev, Elena Meskina, Anna Marova, Alexey Oksanich, Tatiana Samartseva, Georgy Bakhtoyarov, Natalia Bochkareva, Nikolay Filatov, Andrey Linok, Yulia Ammour, Vitaly Zverev

2018, 33(4): 304 doi: 10.1007/s12250-018-0043-0

Received: 23 April 2018 Accepted: 29 June 2018 Published: 30 July 2018
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Enteric viruses are the most common cause of acute gastroenteritis (AGE) in young children and a significant public health problem globally. Hospital admissions of children under 5 years of age with diarrhea are primarily associated with group A rotavirus (RVA) infection. In this retrospective study, the population structure of viruses linked to AGE etiology in young children hospitalized with AGE in Moscow was evaluated, and molecular characterization of RVA strains was performed. Fecal specimens were collected from children under 5 years old hospitalized with AGE between 2009 and 2014 in Moscow, Russia. Multiplex real-time reverse transcription PCR was used to detect enteric viruses and for G/[P]-genotyping of isolated RVAs. Sequencing of RVA VP7 and VP4 cDNA fragments was used to validate the data obtained by PCRgenotyping. The main causes for hospitalization of children with AGE were RVA (40.1%), followed by noroviruses (11.4%), while adenoviruses, astroviruses, sapoviruses, enteroviruses, and orthoreoviruses were detected in 4.7%, 1.9%, 1.4%, 1.2%, and 0.2% of samples tested, respectively. Nosocomial infections, predominantly associated with RVAs and noroviruses, were detected in 24.8% of cases and occurred significantly more frequently in younger infants. The predominant RVA genotype was G4P[8], detected in 38.7% of RVA-positive cases, whereas genotypes G1P[8], G9P[8], G3P[8], and G2P[4] were found in 11.8%, 6.6%, 4.2%, and 3.3% of cases, respectively. Together, the presence of circulating RVA strains with rare VP7 and VP4 gene variants (G6 and P[9]) highlights the need to conduct continuous epidemiological monitoring of RVA infection.

Stress Granule Formation is One of the Early Antiviral Mechanisms for Host Cells Against Coxsackievirus B Infection

Xia Zhai, Shuo Wu, Lexun Lin, Tianying Wang, Xiaoyan Zhong, Yang Chen, Weizhen Xu, Lei Tong, Yan Wang, Wenran Zhao, Zhaohua Zhong

2018, 33(4): 314 doi: 10.1007/s12250-018-0040-3

Received: 19 May 2018 Accepted: 25 May 2018 Published: 29 June 2018
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Stress granules (SGs) are intracellular granules formed when cellular translation is blocked and have been reported to be involved in a variety of viral infections. Our previous studies revealed that SGs are involved in the coxsackievirus B (CVB) infection process, but the role of SGs in CVB infection has not been fully explored. In this study, we found that CVB type 3 (CVB3) induced SG formation in the early phase of infection. Results showed that levels of CVB3 RNA and protein were significantly inhibited during the early stage of CVB3 infection by the promoted formation of SGs, while viral RNA and protein synthesis were significantly promoted when SG formation was blocked by knocking down the SG proteins, G3BP1 and TIA1, separately or in combination. Our findings suggest that SG formation is one of the early antiviral mechanisms for host cells against CVB infection.

Serological Investigation of Laboratory-Confirmed and Suspected Ebola Virus Disease Patients During the Late Phase of the Ebola Outbreak in Sierra Leone

Yang Liu, YuLan Sun, Wei Wu, AQian Li, XianDa Yang, Shuo Zhang, Chuan Li, QiuDong Su, ShaoJian Cai, DaPeng Sun, HaiYang Hu, Zhe Zhang, XiuXu Yang, Idrissa Kamara, Sheku Koroma, Gerald Bangura, Alie Tia, Abdul Kamara, Matt Lebby, Brima Kargbo, Jiandong Li, Shiwen Wang, XiaoPing Dong, YueLong Shu, WenBo Xu, George F. Gao, GuiZhen Wu, DeXin Li, William J. Liu, Liang MiFang

2018, 33(4): 323 doi: 10.1007/s12250-018-0044-z

Received: 30 May 2018 Accepted: 29 June 2018 Published: 31 July 2018
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This study aimed to investigate the serological characteristics of Ebola virus (EBOV) infection during the late phase of the Ebola outbreak in Sierra Leone. In total, 877 blood samples from 694 suspected Ebola virus disease (EVD) cases assessed from March to December 2015, were analyzed via real-time reverse transcription polymerase chain reaction (RT-PCR) for viral RNA and enzyme-linked immunosorbent assay (ELISA) and Luminex to detect antibodies against EBOV. Viral load and EBOV-specific IgM/IgG titers displayed a declining trend during March to December 2015. Viral RNA load decreased rapidly at earlier stages after disease onset, while EBOV-specific IgM and IgG still persisted in 58.1% (18/31) and 93.5% (29/31) of the confirmed EVD patients and in 3.8% (25/663) and 17.8% (118/663) of the RNA-negative suspected patients in the later phase, respectively. Dynamic analysis of longitudinally collected samples from eight EVD patients revealed typically reversed trends of declining viral load and increasing IgM and/or IgG titers in response to the EBOV infection. The present results indicate that certain populations of Sierra Leone developed immunity to an EBOV infection in the late phase of the outbreak, providing novel insights into the risk assessment of EBOV infections among human populations.

Tandem 3' UTR Patterns and Gene Expression Profiles of Marc-145 Cells During PRRSV Infection

Ying Wei, Jie Li, Yun Zhang, Chunyi Xue, Yongchang Cao

2018, 33(4): 335 doi: 10.1007/s12250-018-0045-y

Received: 11 May 2018 Accepted: 04 July 2018 Published: 01 August 2018
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Porcine reproductive and respiratory syndrome virus (PRRSV) causes substantial economic losses to the global pig industry. Alternative polyadenylation (APA) is a mechanism that diversifies gene expression, which is important for tumorigenesis, development, and cell differentiation. However, it is unclear whether APA plays a role in the course of PRRSV infection. To address this issue, in this study we carried out a whole-genome transcriptome analysis of PRRSVinfected Marc-145 African green monkey kidney cells and identified 185 APA switching genes and 393 differentially expressed genes (DEGs). Most of these genes were involved in cellular process, metabolism, and biological regulation, and there was some overlap between the two gene sets. DEGs were found to be more directly involved in the antiviral response than APA genes. These findings provide insight into the dynamics of host gene regulation during PRRSV infection and a basis for elucidating the pathogenesis of PRRSV.

Insights into the Temporal Gene Expression Pattern in Lymantria dispar Larvae During the Baculovirus Induced Hyperactive Stage

Upendra Raj Bhattarai, Mandira Katuwal Bhattarai, Fengjiao Li, Dun Wang

2018, 33(4): 345 doi: 10.1007/s12250-018-0046-x

Received: 28 February 2018 Accepted: 10 July 2018 Published: 25 July 2018
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Baculoviruses are effective biological control agents for many insect pests. They not only efficiently challenge the host immune system but also make them hyperactive for better virus dispersal. Some investigations have focused on the viral mechanisms for induction of such altered response from the host. However, there are no current studies monitoring changes in gene expression during this altered phenotype in infected larvae. The L. dispar multiple nucleopolyhedrovirus (LdMNPV) induces hyperactivity in third instar L. dispar larvae at 3-days post infection (dpi), to continued till 6 dpi. The transcriptome profiles of the infected and uninfected larvae at these time points were analyzed to provide new clues on the response of the larvae towards infection during hyperactivity. Gene ontology enrichment analysis revealed, most of the differentially expressed genes (DEGs) were involved in proteolysis, extracellular region, and serine-type endopeptidase activity. Similarly, Kyoto Encyclopedia of Genes and Genome enrichment analysis showed maximum enrichment of 487 genes of the signal transduction category and neuroactive ligand–receptor interaction sub-category with 85 annotated genes. In addition, enrichment map visualization of gene set enrichment analysis showed the coordinated response of neuroactive ligand–receptor interaction genes with other functional gene sets, as an important signal transduction mechanism during the hyperactive stage. Interestingly all the DEGs in neuroactive ligand–receptor interactions were serine proteases, their differential expression during the hyperactive stage correlated with their conceivable involvement in disease progression and the resulting altered phenotype during this period. The outcome provides a basic understanding of L. dispar larval responses to LdMNPV infection during the hyperactive stage and helps to determine the important host factors involved in this process.

Genome Characteristics of the Cyclophragma Undans Nucleopolyhedrovirus: A Distinct Species in Group Ⅰ of Alphabaculovirus

Zheng Zhu, Jun Wang, Qianran Wang, Feifei Yin, Xiaoping Liu, Dianhai Hou, Lei Zhang, Haizhou Liu, Jiang Li, Basil M. Arif, Hualin Wang, Fei Deng, Zhihong Hu, Manli Wang

2018, 33(4): 359 doi: 10.1007/s12250-018-0047-9

Received: 31 May 2018 Accepted: 16 July 2018 Published: 28 August 2018
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The Cyclophragma undans nucleopolyhedrovirus (CyunNPV), a potential pest control agent, was isolated from Cyclophragma undans (Lepidoptera: Lasiocampidae), an important forest pest. In the present study, we performed detailed genome analysis of CyunNPV and compared its genome to those of other Group I alphabaculoviruses. Sequencing of the CyunNPV genome using the Roche 454 sequencing system generated 142,900 bp with a G+C content of 45%. Genome analysis predicted a total of 147 hypothetical open reading frames (ORFs) comprising 38 baculoviral core genes, 24 lepidopteran baculovirus conserved genes, nine Group I Alphabaculovirus conserved genes, 71 common genes, and five genes that are unique to CyunNPV. In addition, the genome contained 13 homologous repeated sequences (hrs). Phylogenic analysis grouped CyunNPV under a distinct branch within clade "a" of Group I in the genus Alphabaculovirus. Unlike other members of Group I, CyunNPV harbors only nine of the 11 genes previously determined to be specific to Group I viruses. Furthermore, the CyunNPV lacks the tyrosine phosphatase gene and the ac30 gene. The CyunNPV F-like protein contains two insertions of continuous polar amino acids, one at the conventional fusion peptide and a second insertion at the pre-transmembrane domain. The insertions are likely to affect the fusion function and suggest an evolutionary process that led to inactivation of the F-like protein. The above findings implied that CyunNPV is a distinct species under Group I Alphabaculovirus.
Letter

KIR2DL2/C1 is a Risk Factor for Chronic Infection and Associated with Non-response to PEG-IFN and RBV Combination Therapy in Hepatitis C Virus Genotype 1b Patients in China

Song Hu, Fahu Yuan, Lingyan Feng, Fang Zheng, Feili Gong, Hanju Huang, Binlian Sun

2018, 33(4): 369 doi: 10.1007/s12250-018-0042-1

Received: 27 January 2018 Accepted: 14 June 2018 Published: 23 July 2018
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Natural killer (NK) cells play an important role in innate immunity to hepatitis C virus (HCV), especially in response to HCV infections. Killer cell immunoglobulin-like receptors (KIRs) are the primary receptors of NK cells that regulate NK cell behavior to antivirus infection response. Our aim was to determine the association of KIR frequencies with HCV infection and therapy responses in a Chinese Han population, and we compared that of 333 patients infected with HCV-1b and 320 healthy controls, as well as 36 non-responders (NR) and 62 sustained virological responders (SVR) treated with a combination therapy of pegylated alpha interferon and ribavirin. It was found that the frequency of the KIR2DL2 gene was higher in patients infected with HCV than that in controls. Additionally, a higher frequency of the KIR2DL2 gene was observed in NRs compared with SVRs, which was also supported by the results of a meta-analysis. Moreover, in a Chinese Han population, we found that KIR2DL2 in combination with its ligand HLA-C1 is a risk factor for infection and is not useful for HCV therapy; also, the KIR2DL2 gene alone is a risk factor for the development of infection. Results suggested that KIR2DL2 downregulates the killing ability of NK cells in the clearance of HCV.

Molecular Epidemiology of Porcine Circovirus Type 3 Infection in Swine Herds in China

Xiangdong Li, Chaolin Zhang, Mingming Qiao, Jiangsong Guo, Guangyuan Xing, Chunxia Jin, Juan Wang, Ming Sun, Kegong Tian

2018, 33(4): 373 doi: 10.1007/s12250-018-0041-2

Received: 26 April 2018 Accepted: 19 June 2018 Published: 09 July 2018
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Seven hundred thirty clinical tissue samples collected from diseased pigs in South, Middle, and North China were subjected to detect PCV3 DNA by PCR and results showed that PCV3 positive rate was 14.25%. Six PCV3 genomes were obtained and classified into 3 different clusters. The primary PCV3-postive clinical tissues were found to be lung, followed by lymph nodes, stillbirth, kidney, brain, tonsil, spleen, heart, and liver. Of these PCV3-postive samples, PCV2 and PRRSV were primary virus pathogens. The above results showed that PCV3 has widely spread in China and its potential threat to swine industry should be given full consideration.

Serological Cross Reactivity between Zika and Dengue Viruses in Experimentally Infected Monkeys

Shailendra Mani, Chee Wah Tan, Lin-Fa Wang, Danielle E. Anderson

2018, 33(4): 378 doi: 10.1007/s12250-018-0048-8

Received: 11 June 2018 Accepted: 09 August 2018 Published: 28 August 2018
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In the absence of serum panels from individuals with absolute defined infection status, sera from experimentally infected monkeys were generated to cover all four infection scenarios with Zika or dengue virus alone as well as Zika infection followed by dengue and dengue infection followed by Zika. Our data indicated that no currently available single assay platform is sufficiently specific to serologically determine Zika positivity in the presence of prior exposure to dengue and vice versa.