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Mei F, Ren J, Long L, Li J, Li K, Liu H, Tang Y, Fang X, Wu H, Xiao C, Huang T, Deng W. Analysis of HBV X gene quasispecies characteristics by next-generation sequencing and cloning-based sequencing and its association with hepatocellular carcinoma progression. J Med Virol 2019; 91:1087-1096. [PMID: 30712269 DOI: 10.1002/jmv.25421] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 01/22/2019] [Accepted: 01/28/2019] [Indexed: 12/13/2022]
Abstract
OBJECTIVES This study aimed to describe the differences between next-generation sequencing (NGS) and cloning-based sequencing (CBS) in HBX quasispecies research and primitively investigate the relationship between the dominant HBX quasispecies and hepatocellular carcinoma (HCC). METHODS A total of 12 serum samples were collected. Serum hepatitis B virus (HBV) DNA was extracted, and the HBV X-region (HBX) was amplified by nested polymerase chain reaction (PCR). The PCR products were simultaneously tested with NGS and CBS to detect quasispecies of the HBX. RESULTS A total of 9348 eligible quasispecies sequences were obtained by NGS, which were much larger than the 98 of that by CBS. By the phylogenetic tree, the dominant quasispecies sequence of each sample could be found, although they had several nucleotides differences between the dominant quasispecies sequences found by CBS and NGS. By comparing the quasispecies heterogeneity, it was found that the quasispecies complexity value of HBV X-region obtained by NGS was higher than CBS (P < 0.05). The diversity values, including d, dS, dN, an d d N/ dS obtained by NGS were lower than by CBS (all of P < 0.01). The relativity of Spearman(rs) in d, dS, and dN were statistically significant (rs_ d = 0.865, P = 0.001; rs_ dS = 0.722, P = 0.014; and rs_ dN = 0.738, P = 0.011, respectively). There were 21 different bases between the HBX quasispecies of case A and control B. CONCLUSION The results of this can be used as guidance when researchers plan to choose a suitable method to study quasispecies, especially the HBV X gene quasispecies. Some high-risk mutations of HBX quasispecies were also found in this study and their relationship with HCC need deeper exploration.
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Affiliation(s)
- Fanbiao Mei
- Experimental Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jingjing Ren
- Experimental Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Long Long
- The Faculty of Big Data, Guangxi Teachers Education University, Nanning, Guangxi, China
| | - Jilin Li
- Experimental Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Kezhi Li
- Experimental Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Haizhou Liu
- Experimental Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yanping Tang
- Experimental Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiang Fang
- Experimental Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Hanghang Wu
- Experimental Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Chanchan Xiao
- Experimental Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Tianren Huang
- Experimental Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Wei Deng
- Experimental Research Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
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2
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Zhu YO, Aw PPK, de Sessions PF, Hong S, See LX, Hong LZ, Wilm A, Li CH, Hue S, Lim SG, Nagarajan N, Burkholder WF, Hibberd M. Single-virion sequencing of lamivudine-treated HBV populations reveal population evolution dynamics and demographic history. BMC Genomics 2017; 18:829. [PMID: 29078745 PMCID: PMC5660452 DOI: 10.1186/s12864-017-4217-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 10/16/2017] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Viral populations are complex, dynamic, and fast evolving. The evolution of groups of closely related viruses in a competitive environment is termed quasispecies. To fully understand the role that quasispecies play in viral evolution, characterizing the trajectories of viral genotypes in an evolving population is the key. In particular, long-range haplotype information for thousands of individual viruses is critical; yet generating this information is non-trivial. Popular deep sequencing methods generate relatively short reads that do not preserve linkage information, while third generation sequencing methods have higher error rates that make detection of low frequency mutations a bioinformatics challenge. Here we applied BAsE-Seq, an Illumina-based single-virion sequencing technology, to eight samples from four chronic hepatitis B (CHB) patients - once before antiviral treatment and once after viral rebound due to resistance. RESULTS With single-virion sequencing, we obtained 248-8796 single-virion sequences per sample, which allowed us to find evidence for both hard and soft selective sweeps. We were able to reconstruct population demographic history that was independently verified by clinically collected data. We further verified four of the samples independently through PacBio SMRT and Illumina Pooled deep sequencing. CONCLUSIONS Overall, we showed that single-virion sequencing yields insight into viral evolution and population dynamics in an efficient and high throughput manner. We believe that single-virion sequencing is widely applicable to the study of viral evolution in the context of drug resistance and host adaptation, allows differentiation between soft or hard selective sweeps, and may be useful in the reconstruction of intra-host viral population demographic history.
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Affiliation(s)
- Yuan O Zhu
- Genome Institute of Singapore, Singapore, 138672, Singapore.
| | - Pauline P K Aw
- Genome Institute of Singapore, Singapore, 138672, Singapore
| | | | - Shuzhen Hong
- Genome Institute of Singapore, Singapore, 138672, Singapore
| | - Lee Xian See
- Institute of Molecular and Cell Biology, Singapore, 138673, Singapore
| | - Lewis Z Hong
- Institute of Molecular and Cell Biology, Singapore, 138673, Singapore
| | - Andreas Wilm
- Genome Institute of Singapore, Singapore, 138672, Singapore
| | - Chen Hao Li
- Genome Institute of Singapore, Singapore, 138672, Singapore
| | - Stephane Hue
- London School of Hygiene and Tropical Medicine, London, UK
| | - Seng Gee Lim
- National University Hospital, Singapore, 119074, Singapore
| | | | | | - Martin Hibberd
- Genome Institute of Singapore, Singapore, 138672, Singapore.,London School of Hygiene and Tropical Medicine, London, UK
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3
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Wu Q, Xu C, Li J, Li L, Yan G, Yue L, Zeng Y, Huang H, Deng G, Wang Y. Evolution and mutations of hepatitis B virus quasispecies in genotype B and C during vertical transmission. J Med Virol 2015; 88:1018-26. [PMID: 26531675 DOI: 10.1002/jmv.24424] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/02/2015] [Indexed: 12/15/2022]
Abstract
Evolution patterns of HBV QS between genotype B and C during vertical transmission are not well understood. In this study, we enrolled 10 HBV infected mother-infant pairs (four pairs with genotype B, four pairs with genotype C, and two with co-infection) without anti-viral therapy. Serum HBV DNA of mothers and infants were sequenced, HBV QS complexity and diversity were analyzed, polymorphisms and mutation sites were recorded, and phylogenetic trees were performed. Our result showed that the QS complexities in P (amino acid), C/PreC (amino acid), and PreS1 (nucleotide) gene were significantly higher in mothers than in infants in pairs with genotype C (P < 0.05), however, full-length and other genes showed non-significant differences (P > 0.05). Unlike genotype C, QS complexity of P gene (nucleotide) was significantly higher in infants than in mothers (P < 0.05) in pairs with genotype B, similarly, QS complexities of full-length and other genes (except Pre S2) were also higher in infants than in mothers but without significant differences (P > 0.05). QS diversities of full-length and most genes in genotype B were comparable between mothers and their infants (P > 0.05), in pairs with genotype C, dS of P, X, RT genes, genetic distance of Pre S1 gene (amino acid) and dN of Pre S1 gene were significant higher in mothers than in infants (P < 0.05). Several HBV mutations correlated with immune escape, e antigen loss and drug resistance were observed in infants. The results indicated that differences of HBV QS evolution patterns between genotype B and C during vertical transmission might contribute to distinct prognosis.
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Affiliation(s)
- Quanxin Wu
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.,The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China.,Cadre Ward Two, Wuhan General Hospital of Guangzhou Military Command, Wuhan, China
| | - Cheng Xu
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.,The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China
| | - Junnan Li
- Department of Gynecology and Obstetrics, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Li Li
- Department of Gynecology and Obstetrics, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Guohua Yan
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.,The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China
| | - Liangliang Yue
- National Plateau Wetland Research Center, Southwest Forest University, Kunming, China
| | - Yi Zeng
- Department of Gynecology and Obstetrics, The First People's Hospital, Zigong, Sichuan, China
| | - Hongfei Huang
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.,The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China
| | - Guohong Deng
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.,The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China
| | - Yuming Wang
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.,The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China
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Tao XY, Tang Q, Rayner S, Guo ZY, Li H, Lang SL, Yin CP, Han N, Fang W, Adams J, Song M, Liang GD. Molecular phylodynamic analysis indicates lineage displacement occurred in Chinese rabies epidemics between 1949 to 2010. PLoS Negl Trop Dis 2013; 7:e2294. [PMID: 23875035 PMCID: PMC3708843 DOI: 10.1371/journal.pntd.0002294] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Accepted: 05/20/2013] [Indexed: 12/25/2022] Open
Abstract
Rabies remains a serious problem in China with three epidemics since 1949 and the country in the midst of the third epidemic. Significantly, the control of each outbreak has been followed by a rapid reemergence of the disease. In 2005, the government implemented a rabies national surveillance program that included the collection and screening of almost 8,000 samples. In this work, we analyzed a Chinese dataset comprising 320 glycoprotein sequences covering 23 provinces and eight species, spanning the second and third epidemics. Specifically, we investigated whether the three epidemics are associated with a single reemerging lineage or a different lineage was responsible for each epidemic. Consistent with previous results, phylogenetic analysis identified six lineages, China I to VI. Analysis of the geographical composition of these lineages revealed they are consistent with human case data and reflect the gradual emergence of China I in the third epidemic. Initially, China I was restricted to south China and China II was dominant. However, as the epidemic began to spread into new areas, China I began to emerge, whereas China II remained confined to south China. By the latter part of the surveillance period, almost all isolates were China I and contributions from the remaining lineages were minimal. The prevalence of China II in the early stages of the third epidemic and its established presence in wildlife suggests that it too replaced a previously dominant lineage during the second epidemic. This lineage replacement may be a consequence of control programs that were dominated by dog culling efforts as the primary control method in the first two epidemics. This had the effect of reducing dominant strains to levels comparable with other localized background stains. Our results indicate the importance of effective control strategies for long term control of the disease. Since 1949, there have been three rabies epidemics in China. The country is currently in the midst of a third epidemic. After the first two epidemics were brought under control, there was a rapid reemergence of the disease. In 2005, the government implemented a national surveillance program and as part of this work, samples were collected from humans and animals and screened for rabies. Positive samples were sequenced and combined with other publicly available sequences to form a dataset that spanned almost all epidemic regions in China. A phylogenetic tree was constructed the clustering of isolates according to geographic origin and lineage was investigated. We found that most isolates were grouped into two lineages China I and China II. However, the proportion of isolates in these lineages changed over time until almost all new isolates were placed in China I, indicating it has emerged as the dominant lineage. Furthermore, the significantly higher number of China II isolates compared to remaining lineages together with its established presence in wildlife suggests that it was dominant in the second epidemic, suggesting that lineage replacement also occurred during the previous epidemic.
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Affiliation(s)
- Xiao-Yan Tao
- State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Qing Tang
- State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
- * E-mail: (QT); (SR)
| | - Simon Rayner
- Key Laboratory of Agricultural and Environmental Microbiology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
- * E-mail: (QT); (SR)
| | - Zhen-Yang Guo
- State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
- Key Laboratory of Agricultural and Environmental Microbiology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Hao Li
- State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Shu-Lin Lang
- State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Cui-Ping Yin
- State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Na Han
- Key Laboratory of Agricultural and Environmental Microbiology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Wei Fang
- Key Laboratory of Agricultural and Environmental Microbiology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - James Adams
- Key Laboratory of Agricultural and Environmental Microbiology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Miao Song
- State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
- Liupanshui Vocational and Technical College, Liupanshui, Guizhou, China
| | - Guo-Dong Liang
- State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
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5
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Jeulin H, Velay A, Murray J, Schvoerer E. Clinical impact of hepatitis B and C virus envelope glycoproteins. World J Gastroenterol 2013; 19:654-664. [PMID: 23429668 PMCID: PMC3574591 DOI: 10.3748/wjg.v19.i5.654] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 12/17/2012] [Indexed: 02/06/2023] Open
Abstract
Chronic infection by either hepatitis B virus (HBV) or hepatitis C virus (HCV) share epidemiological characteristics with risks for development of severe complications such as liver cirrhosis and hepatocellular carcinoma. HBV and HCV also share a high genetic variability. Among highly variable regions, viral genes encoding surface proteins (hepatitis B surface antigen, E1/E2 HCV glycoproteins) play key roles in the stimulation of the host-related immune response and viral entry into hepatocytes. Specific segments of HBV envelope proteins (preS1, “a” determinant) are crucial in the entry process into permissive cells. HCV entry is a complex multistep process involving multiple cell cofactors (glycosaminoglycans, low density lipoprotein receptor, SR-B1, CD81, claudin-1, occludin, EGFR, EphA2) in the interaction with HCV E1/E2 envelope glycoproteins. In vitro both viruses can be controlled by antibody-mediated neutralization targeting viral envelope, also essential in preventing HBV infection in vivo as observed through successful vaccination using HBs antigen. But preventive vaccination and/or therapeutic pressure can influence HBV and HCV variability. For HBV, the patterns of antiviral drug resistance in chronic hepatitis are complex and the original pol/S gene overlap has to be taken into account. Treatment-induced HBV mutations in pol could indeed generate S mutants with subsequent modified antigenicity or increased cancer induction. Variability of HBV and HCV envelope proteins combining high exposure to selective pressures and crucial functional roles require investigation in the context of diagnostic, vaccination and treatment tools. In this editorial a synthesis is performed of HBV and HCV envelope properties at the entry step and as antigenic proteins, and the subsequent clinical impact.
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MESH Headings
- Animals
- Antiviral Agents/therapeutic use
- Drug Resistance, Viral
- Genotype
- Hepacivirus/drug effects
- Hepacivirus/genetics
- Hepacivirus/immunology
- Hepacivirus/metabolism
- Hepacivirus/pathogenicity
- Hepatitis B Vaccines
- Hepatitis B virus/drug effects
- Hepatitis B virus/genetics
- Hepatitis B virus/immunology
- Hepatitis B virus/metabolism
- Hepatitis B virus/pathogenicity
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/prevention & control
- Hepatitis B, Chronic/virology
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/prevention & control
- Hepatitis C, Chronic/virology
- Host-Pathogen Interactions
- Humans
- Phenotype
- Prognosis
- Viral Envelope Proteins/genetics
- Viral Envelope Proteins/metabolism
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Chook JB, Ngeow YF, Khang TF, Ng KP, Tiang YP, Mohamed R. Comparative analysis of viral genomes from acute and chronic hepatitis B reveals novel variants associated with a lower rate of chronicity. J Med Virol 2013; 85:419-24. [PMID: 23297244 DOI: 10.1002/jmv.23500] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2012] [Indexed: 01/05/2023]
Abstract
Infection with the hepatitis B virus (HBV) may lead to an acute or chronic infection. It is generally accepted that the clinical outcome of infection depends on the balance between host immunity and viral survival strategies. In order to persist, the virus needs to have a high rate of replication and some immune-escape capabilities. Hence, HBVs lacking these properties are likely to be eliminated more rapidly by the host, leading to a lower rate of chronicity. To test this hypothesis, 177 HBV genomes from acute non-fulminant cases and 1,149 from chronic cases were retrieved from GenBank for comparative analysis. Selection of candidate nucleotides associated with the disease state was done using random guess cut-off and the Bonferroni correction. Five significant nucleotides were detected using this filtering step. Their predictive values were assessed using the support vector machine classification with five-fold cross-validation. The average prediction accuracy was 61% ± 1%, with a sensitivity of 24% ± 1%, specificity of 98% ± 1%, positive predictive value of 92% ± 4% and negative predictive value of 56% ± 1%. BCP/X, enhancer I and surface/polymerase variants were found to be associated almost exclusively with acute hepatitis. These HBV variants are novel potential markers for non-progression to chronic hepatitis.
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Affiliation(s)
- Jack Bee Chook
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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7
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Homs M, Buti M, Tabernero D, Quer J, Sanchez A, Corral N, Esteban R, Rodriguez-Frias F. Quasispecies dynamics in main core epitopes of hepatitis B virus by ultra-deep-pyrosequencing. World J Gastroenterol 2012; 18:6096-105. [PMID: 23155338 PMCID: PMC3496886 DOI: 10.3748/wjg.v18.i42.6096] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Revised: 07/25/2012] [Accepted: 07/28/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the variability of the main immunodominant motifs of hepatitis B virus (HBV) core gene by ultra-deep-pyrosequencing (UDPS).
METHODS: Four samples (2 genotype A and 2 genotype D) from 4 treatment-naïve patients were assessed for baseline variability. Two additional samples from one patient (patient 4, genotype D) were selected for analysis: one sample corresponded to a 36-mo treatment-free period from baseline and the other to the time of viral breakthrough after 18 mo of lamivudine treatment. The HBV region analyzed covered amino acids 40 to 95 of the core gene, and included the two main epitopic regions, Th50-69 and B74-84. UDPS was carried out in the Genome Sequencer FLX system (454 Life Sciences, Roche). After computer filtering of UDPS data based on a Poisson statistical model, 122 813 sequences were analyzed. The most conserved position detected by UDPS was analyzed by site-directed mutagenesis and evaluated in cell culture.
RESULTS: Positions with highest variability rates were mainly located in the main core epitopes, confirming their role as immune-stimulating regions. In addition, the distribution of variability showed a relationship with HBV genotype. Patient 1 (genotype A) presented the lowest variability rates and patient 2 (genotype A) had 3 codons with variability higher than 1%. Patient 3 and 4 (both genotype D) presented 5 and 8 codons with variability higher than 1%, respectively. The median baseline frequencies showed that genotype A samples had higher variability in epitopic positions than in the other positions analyzed, approaching significance (P = 0.07, sample 1 and P = 0.05, sample 2). In contrast, there were no significant differences in variability between the epitopic and other positions in genotype D cases. Interestingly, patient 1 presented a completely mutated motif from amino acid 64 to 67 (E64LMT67), which is commonly recognized by T helper cells. Additionally, the variability observed in all 4 patients was particularly associated with the E64LMT67 motif. Codons 78 and 79 were highly conserved in all samples, in keeping with their involvement in the interaction between the HBV virion capsid and the surface antigens (HBsAg). Of note, codon 76 was even more conserved than codons 78 and 79, suggesting a possible role in HBsAg interactions or even in hepatitis B e antigen conformation. Sequential analysis of samples from patient 4 (genotype D) illustrated the dynamism of the HBV quasispecies, with strong selection of one minor baseline variant coinciding with a decrease in core variability during the treatment-free and lamivudine-treated period. The drop in variability seemed to result from a “steady state” situation of the HBV quasispecies after selection of the variant with greatest fitness.
CONCLUSION: Host immune pressure seems to be the main cause of HBV core evolution. UDPS analysis is a useful technique for studying viral quasispecies.
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Abstract
Evolution of RNA viruses occurs through disequilibria of collections of closely related mutant spectra or mutant clouds termed viral quasispecies. Here we review the origin of the quasispecies concept and some biological implications of quasispecies dynamics. Two main aspects are addressed: (i) mutant clouds as reservoirs of phenotypic variants for virus adaptability and (ii) the internal interactions that are established within mutant spectra that render a virus ensemble the unit of selection. The understanding of viruses as quasispecies has led to new antiviral designs, such as lethal mutagenesis, whose aim is to drive viruses toward low fitness values with limited chances of fitness recovery. The impact of quasispecies for three salient human pathogens, human immunodeficiency virus and the hepatitis B and C viruses, is reviewed, with emphasis on antiviral treatment strategies. Finally, extensions of quasispecies to nonviral systems are briefly mentioned to emphasize the broad applicability of quasispecies theory.
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Affiliation(s)
- Esteban Domingo
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), C/ Nicolás Cabrera, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
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