Publications
343 results found
Phan VTM, Rabaa MA, Donato C, et al., 2014, Novel porcine-like human G26P[19] rotavirus identified in hospitalized paediatric diarrhoea patients in Ho Chi Minh City, Vietnam, Journal of General Virology, Vol: 95, Pages: 2727-2733, ISSN: 1465-2099
During a hospital-based diarrhoeal disease study conducted in Ho Chi Minh City, Vietnam from 2009 to 2010, we identified four symptomatic children infected with G26P[19] rotavirus (RV) – an atypical variant that has not previously been reported in human gastroenteritis. To determine the genetic structure and investigate the origin of this G26P[19] strain, the whole genome of a representative example was characterized, revealing a novel genome constellation: G26–P[19]–I5–R1–C1–M1–A8–N1–T1–E1–H1. The genome segments were most closely related to porcine (VP7, VP4, VP6 and NSP1) and Wa-like porcine RVs (VP1–3 and NSP2–5). We proposed that this G26P[19] strain was the product of zoonotic transmission coupled with one or more reassortment events occurring in human and/or animal reservoirs. The identification of such strains has potential implications for vaccine efficacy in south-east Asia, and outlines the utility of whole-genome sequencing for studying RV diversity and zoonotic potential during disease surveillance.
Memish ZA, Al-Tawfiq JA, Makhdoom HQ, et al., 2014, Respiratory tract samples, viral load, and genome fraction yield in patients with Middle East Respiratory Syndrome, Journal of Infectious Diseases, Vol: 210, Pages: 1590-1594, ISSN: 0022-1899
Background. Analysis of clinical samples from patients with new viral infections is critical to confirm the diagnosis, to specify the viral load, and to sequence data necessary for characterizing the viral kinetics, transmission, and evolution. We analyzed samples from 112 patients infected with the recently discovered Middle East respiratory syndrome coronavirus (MERS-CoV).Methods. Respiratory tract samples from cases of MERS-CoV infection confirmed by polymerase chain reaction (PCR) were investigated to determine the MERS-CoV load and fraction of the MERS-CoV genome. These values were analyzed to determine associations with clinical sample type.Results. Samples from 112 individuals in which MERS-CoV was detected by PCR were analyzed, of which 13 were sputum samples, 64 were nasopharyngeal swab specimens, 30 were tracheal aspirates, and 3 were bronchoalveolar lavage specimens; 2 samples were of unknown origin. Tracheal aspirates yielded significantly higher MERS-CoV loads, compared with nasopharyngeal swab specimens (P = .005) and sputum specimens (P = .0001). Tracheal aspirates had viral loads similar to those in bronchoalveolar lavage samples (P = .3079). Bronchoalveolar lavage samples and tracheal aspirates had significantly higher genome fraction than nasopharyngeal swab specimens (P = .0095 and P = .0002, respectively) and sputum samples (P = .0009 and P = .0001, respectively). The genome yield from tracheal aspirates and bronchoalveolar lavage samples were similar (P = .1174).Conclusions. Lower respiratory tract samples yield significantly higher MERS-CoV loads and genome fractions than upper respiratory tract samples.
Elderfield RA, Watson SJ, Godlee A, et al., 2014, Accumulation of human-adapting mutations during circulation of A(H1N1)pdm09 influenza virus in humans in the United Kingdom, Journal of Virology, Vol: 88, Pages: 13269-13283, ISSN: 0022-538X
The influenza pandemic that emerged in 2009 provided an unprecedented opportunity to study adaptation of a virus recently acquired from an animal source during human transmission. In the United Kingdom, the novel virus spread in three temporally distinct waves between 2009 and 2011. Phylogenetic analysis of complete viral genomes showed that mutations accumulated over time. Second- and third-wave viruses replicated more rapidly in human airway epithelial (HAE) cells than did the first-wave virus. In infected mice, weight loss varied between viral isolates from the same wave but showed no distinct pattern with wave and did not correlate with viral load in the mouse lungs or severity of disease in the human donor. However, second- and third-wave viruses induced less alpha interferon in the infected mouse lungs. NS1 protein, an interferon antagonist, had accumulated several mutations in second- and third-wave viruses. Recombinant viruses with the third-wave NS gene induced less interferon in human cells, but this alone did not account for increased virus fitness in HAE cells. Mutations in HA and NA genes in third-wave viruses caused increased binding to α-2,6-sialic acid and enhanced infectivity in human mucus. A recombinant virus with these two segments replicated more efficiently in HAE cells. A mutation in PA (N321K) enhanced polymerase activity of third-wave viruses and also provided a replicative advantage in HAE cells. Therefore, multiple mutations allowed incremental changes in viral fitness, which together may have contributed to the apparent increase in severity of A(H1N1)pdm09 influenza virus during successive waves.
Guiliano DB, Fussell H, Lenart I, et al., 2014, Endoplasmic Reticulum Degradation-Enhancing α-Mannosidase-like Protein 1 Targets Misfolded HLA-B27 Dimers for Endoplasmic Reticulum-Associated Degradation, ARTHRITIS & RHEUMATOLOGY, Vol: 66, Pages: 2976-2988, ISSN: 2326-5191
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- Citations: 32
Houldcroft CJ, Petrova V, Liu JZ, et al., 2014, Host genetic variants and gene expression patterns associated with Epstein-Barr virus copy number in lymphoblastoid cell lines, PLoS ONE, Vol: 9, ISSN: 1932-6203
Lymphoblastoid cell lines (LCLs) are commonly used in molecular genetics, supplying DNA for the HapMap and 1000 Genomes Projects, used to test chemotherapeutic agents, and informing the basis of a number of population genetics studies of gene expression. The process of transforming human B cells into LCLs requires the presence of Epstein-Barr virus (EBV), a double-stranded DNA virus which through B-cell immortalisation maintains an episomal virus genome in every cell of an LCL at variable copy numbers. Previous studies have reported that EBV alters host-gene expression and EBV copy number may be under host genetic control. We performed a genome-wide association study of EBV genome copy number in LCLs and found the phenotype to be highly heritable, although no individual SNPs achieved a significant association with EBV copy number. The expression of two host genes (CXCL16 and AGL) was positively correlated and expression of ADARB2 was negatively correlated with EBV copy number in a genotype-independent manner. This study shows an association between EBV copy number and the gene expression profile of LCLs, and suggests that EBV copy number should be considered as a covariate in future studies of host gene expression in LCLs.
Madani TA, Azhar EI, Hashem AM, 2014, Evidence for Camel-to-Human Transmission of MERS Coronavirus Reply, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 371, Pages: 1360-1360, ISSN: 0028-4793
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- Citations: 668
Drosten C, Kellam P, Memish ZA, 2014, Evidence for Camel-to-Human Transmission of MERS Coronavirus, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 371, Pages: 1359-1360, ISSN: 0028-4793
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- Citations: 668
Brener J, Gall A, Batorsky R, et al., 2014, HIV Minor Variants Detected by Next Generation Sequencing: Impact on Immune Control of HIV in the Context of HLA-B*27:05 and HLA-B*57:01, Symposium on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: A180-A181, ISSN: 0889-2229
Dennis AM, Herbeck JT, Brown AL, et al., 2014, Phylogenetic Studies of Transmission Dynamics in Generalized HIV Epidemics: An Essential Tool Where the Burden is Greatest?, JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES, Vol: 67, Pages: 181-195, ISSN: 1525-4135
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- Citations: 68
Bracke L, Willems E, Gall A, et al., 2014, Characterisation of Transmitted and Non-transmitted HIV in Index-recipient Transmission Pairs, Symposium on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: A224-A225, ISSN: 0889-2229
Archer EJ, Bashford-Rogers R, Hill B, et al., 2014, Evolution of Antigen-specific B-cell Receptor Repertoires in Early SIV Infection, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A19-A19, ISSN: 0889-2229
Cotten M, Petrova V, Phan MVT, et al., 2014, Deep sequencing of norovirus genomes defines evolutionary patterns in an urban tropical setting, Journal of Virology, Vol: 88, Pages: 11056-11069, ISSN: 1098-5514
Norovirus is a highly transmissible infectious agent that causes epidemic gastroenteritis in susceptible children and adults. Norovirus infections can be severe and can be initiated from an exceptionally small number of viral particles. Detailed genome sequence data are useful for tracking norovirus transmission and evolution. To address this need, we have developed a whole-genome deep-sequencing method that generates entire genome sequences from small amounts of clinical specimens. This novel approach employs an algorithm for reverse transcription and PCR amplification primer design using all of the publically available norovirus sequence data. Deep sequencing and de novo assembly were used to generate norovirus genomes from a large set of diarrheal patients attending three hospitals in Ho Chi Minh City, Vietnam, over a 2.5-year period. Positive-selection analysis and direct examination of protein changes in the virus over time identified codons in the regions encoding proteins VP1, p48 (NS1-2), and p22 (NS4) under positive selection and expands the known targets of norovirus evolutionary pressure.
Cheung PPH, Watson SJ, Choy K-T, et al., 2014, Generation and characterization of influenza A viruses with altered polymerase fidelity, Nature Communications, Vol: 5, ISSN: 2041-1723
Genetic diversity of influenza A viruses (IAV) acquired through the error-prone RNA-dependent RNA polymerase (RdRP) or through genetic reassortment enables perpetuation of IAV in humans through epidemics or pandemics. Here, to assess the biological significance of genetic diversity acquired through RdRP, we characterize an IAV fidelity variant derived from passaging a seasonal H3N2 virus in the presence of ribavirin, a purine analogue that increases guanosine-to-adenosine mutations. We demonstrate that a single PB1-V43I mutation increases selectivity to guanosine in A/Wuhan/359/95 (H3N2) and A/Vietnam/1203/04 (H5N1) viruses. The H5N1 PB1-V43I-recombinant virus replicates to comparable titres as the wild-type virus in vitro or in the mouse lungs. However, a decrease in viral population diversity at day 3 post inoculation is associated with a tenfold reduced lethality and neurotropism in mice. Applying a fidelity variant with reduced mutational frequency, we provide direct experimental evidence for the role of genetic diversity in IAV pathogenesis.
Kwok H, Wu CW, Palser AL, et al., 2014, Genomic Diversity of Epstein-Barr Virus Genomes Isolated from Primary Nasopharyngeal Carcinoma Biopsy Samples, JOURNAL OF VIROLOGY, Vol: 88, Pages: 10662-10672, ISSN: 0022-538X
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- Citations: 83
Takebe Y, Naito Y, Raghwani J, et al., 2014, Intercontinental Dispersal of HIV-1 Subtype B Associated with Transmission among Men Who Have Sex with Men in Japan, JOURNAL OF VIROLOGY, Vol: 88, Pages: 9864-9876, ISSN: 0022-538X
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- Citations: 17
Hue S, Brown AE, Ragonnet-Cronin M, et al., 2014, Phylogenetic analyses reveal HIV-1 infections between men misclassified as heterosexual transmissions, AIDS, Vol: 28, Pages: 1967-1975, ISSN: 0269-9370
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- Citations: 59
Weston S, Czieso S, White IJ, et al., 2014, A membrane topology model for human interferon inducible transmembrane protein 1, PLoS ONE, Vol: 9, ISSN: 1932-6203
InterFeron Inducible TransMembrane proteins 1–3 (IFITM1, IFITM2 and IFITM3) are a family of proteins capable of inhibiting the cellular entry of numerous human and animal viruses. IFITM1-3 are unique amongst the currently described viral restriction factors in their apparent ability to block viral entry. This restrictive property is dependant on the localisation of the proteins to plasma and endosomal membranes, which constitute the main portals of viral entry into cells. The topology of the IFITM proteins within cell membranes is an unresolved aspect of their biology. Here we present data from immunofluorescence microscopy, protease cleavage, biotin-labelling and immuno-electron microscopy assays, showing that human IFITM1 has a membrane topology in which the N-terminal domain resides in the cytoplasm, and the C-terminal domain is extracellular. Furthermore, we provide evidence that this topology is conserved for all of the human interferon-induced IFITM proteins. This model is consistent with that recently proposed for murine IFITM3, but differs from that proposed for murine IFITM1.
Bashford-Rogers RJM, Palser AL, Idris SF, et al., 2014, Capturing needles in haystacks: a comparison of B-cell receptor sequencing methods, BMC Immunology, Vol: 15, ISSN: 1471-2172
BackgroundDeep-sequencing methods are rapidly developing in the field of B-cell receptor (BCR) and T-cell receptor (TCR) diversity. These promise to revolutionise our understanding of adaptive immune dynamics, identify novel antibodies, and allow monitoring of minimal residual disease. However, different methods for BCR and TCR enrichment and amplification have been proposed. Here we perform the first systematic comparison between different methods of enrichment, amplification and sequencing for generating BCR and TCR repertoires using large sample numbers.ResultsResampling from the same RNA or cDNA pool results in highly correlated and reproducible repertoires, but resampling low frequency clones leads to stochastic variance. Repertoires generated by different sequencing methods (454 Roche and Illumina MiSeq) and amplification methods (multiplex PCR, 5’ Rapid amplification of cDNA ends (5’RACE), and RNA-capture) are highly correlated, and resulting IgHV gene frequencies between the different methods were not significantly different. Read length has an impact on captured repertoire structure, and ultimately full-length BCR sequences are most informative for repertoire analysis as diversity outside of the CDR is very useful for phylogenetic analysis. Additionally, we show RNA-based BCR repertoires are more informative than using DNA.ConclusionsRepertoires generated by different sequencing and amplification methods are consistent, but we show that read lengths, depths and error profiles should be considered in experimental design, and multiple sampling approaches could be employed to minimise stochastic sampling variation. This detailed investigation of immune repertoire sequencing methods is essential for informing basic and clinical research.
Bouwman RD, Palser A, Parry CM, et al., 2014, Human immunodeficiency virus Tat associates with a specific set of cellular RNAs, Retrovirology, Vol: 11, ISSN: 1742-4690
BackgroundHuman Immunodeficiency Virus 1 (HIV-1) exhibits a wide range of interactions with the host cell but whether viral proteins interact with cellular RNA is not clear. A candidate interacting factor is the trans-activator of transcription (Tat) protein. Tat is required for expression of virus genes but activates transcription through an unusual mechanism; binding to an RNA stem-loop, the transactivation response element (TAR), with the host elongation factor P-TEFb. HIV-1 Tat has also been shown to alter the expression of host genes during infection, contributing to viral pathogenesis but, whether Tat also interacts with cellular RNAs is unknown.ResultsUsing RNA immunoprecipitation coupled with microarray analysis, we have discovered that HIV-1 Tat is associated with a specific set of human mRNAs in T cells. mRNAs bound by Tat share a stem-loop structural element and encode proteins with common biological roles. In contrast, we do not find evidence that Tat associates with microRNAs or the RNA-induced silencing complex (RISC). The interaction of Tat with cellular RNA requires an intact RNA binding domain and Tat RNA binding is linked to an increase in RNA abundance in cell lines and during infection of primary CD4+ T cells by HIV.ConclusionsWe conclude that Tat interacts with a specific set of human mRNAs in T cells, many of which show changes in abundance in response to Tat and HIV infection. This work uncovers a previously unrecognised interaction between HIV and its host that may contribute to viral alteration of the host cellular environment.
Azhar EI, El-Kafrawy SA, Farraj SA, et al., 2014, Evidence for Camel-to-Human Transmission of MERS Coronavirus, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 370, Pages: 2499-2505, ISSN: 0028-4793
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- Citations: 668
Memish ZA, Cotten M, Watson SJ, et al., 2014, Community case clusters of Middle East respiratory syndrome coronavirus in Hafr Al-Batin, Kingdom of Saudi Arabia: A descriptive genomic study, International Journal of Infectious Diseases, Vol: 23, Pages: 63-68, ISSN: 1201-9712
The Middle East respiratory syndrome coronavirus (MERS-CoV) was first described in September 2012 and to date 86 deaths from a total of 206 cases of MERS-CoV infection have been reported to the WHO. Camels have been implicated as the reservoir of MERS-CoV, but the exact source and mode of transmission for most patients remain unknown. During a 3 month period, June to August 2013, there were 12 positive MERS-CoV cases reported from the Hafr Al-Batin region district in the north east region of the Kingdom of Saudi Arabia. In addition to the different regional camel festivals in neighboring countries, Hafr Al-Batin has the biggest camel market in the entire Kingdom and hosts an annual camel festival. Thus, we conducted a detailed epidemiological, clinical and genomic study to ascertain common exposure and transmission patterns of all cases of MERS-CoV reported from Hafr Al-Batin. Analysis of previously reported genetic data indicated that at least two of the infected contacts could not have been directly infected from the index patient and alternate source should be considered. While camels appear as the likely source, other sources have not been ruled out. More detailed case control studies with detailed case histories, epidemiological information and genomic analysis are being conducted to delineate the missing pieces in the transmission dynamics of MERS-CoV outbreak.
Memish ZA, Cotten M, Meyer B, et al., 2014, Human infection with MERS Coronavirus after exposure to infected camels, Saudi Arabia, 2013, Emerging Infectious Diseases, Vol: 20, Pages: 1012-1015, ISSN: 1080-6040
We investigated a case of human infection with Middle East respiratory syndrome coronavirus (MERS-CoV) after exposure to infected camels. Analysis of the whole human-derived virus and 15% of the camel-derived virus sequence yielded nucleotide polymorphism signatures suggestive of cross-species transmission. Camels may act as a direct source of human MERS-CoV infection.
Hodcroft E, Hadfield JD, Fearnhill E, et al., 2014, The contribution of viral genotype to plasma viral set-point in HIV infection, PLoS Pathogens, Vol: 10, ISSN: 1553-7366
Disease progression in HIV-infected individuals varies greatly, and while the environmental and host factors influencing this variation have been widely investigated, the viral contribution to variation in set-point viral load, a predictor of disease progression, is less clear. Previous studies, using transmission-pairs and analysis of phylogenetic signal in small numbers of individuals, have produced a wide range of viral genetic effect estimates. Here we present a novel application of a population-scale method based in quantitative genetics to estimate the viral genetic effect on set-point viral load in the UK subtype B HIV-1 epidemic, based on a very large data set. Analyzing the initial viral load and associated pol sequence, both taken before anti-retroviral therapy, of 8,483 patients, we estimate the proportion of variance in viral load explained by viral genetic effects to be 5.7% (CI 2.8–8.6%). We also estimated the change in viral load over time due to selection on the virus and environmental effects to be a decline of 0.05 log10 copies/mL/year, in contrast to recent studies which suggested a reported small increase in viral load over the last 20 years might be due to evolutionary changes in the virus. Our results suggest that in the UK epidemic, subtype B has a small but significant viral genetic effect on viral load. By allowing the analysis of large sample sizes, we expect our approach to be applicable to the estimation of the genetic contribution to traits in many organisms.
Cotten M, Munnink BO, Canuti M, et al., 2014, Full genome virus detection in fecal samples using sensitive nucleic acid preparation, deep sequencing, and a novel iterative sequence classification algorithm, PLoS ONE, Vol: 9, ISSN: 1932-6203
We have developed a full genome virus detection process that combines sensitive nucleic acid preparation optimised for virus identification in fecal material with Illumina MiSeq sequencing and a novel post-sequencing virus identification algorithm. Enriched viral nucleic acid was converted to double-stranded DNA and subjected to Illumina MiSeq sequencing. The resulting short reads were processed with a novel iterative Python algorithm SLIM for the identification of sequences with homology to known viruses. De novo assembly was then used to generate full viral genomes. The sensitivity of this process was demonstrated with a set of fecal samples from HIV-1 infected patients. A quantitative assessment of the mammalian, plant, and bacterial virus content of this compartment was generated and the deep sequencing data were sufficient to assembly 12 complete viral genomes from 6 virus families. The method detected high levels of enteropathic viruses that are normally controlled in healthy adults, but may be involved in the pathogenesis of HIV-1 infection and will provide a powerful tool for virus detection and for analyzing changes in the fecal virome associated with HIV-1 progression and pathogenesis.
Dunn D, 2014, The increasing genetic diversity of HIV-1 in the UK, 2002-2010, AIDS, Vol: 28, Pages: 773-780, ISSN: 0269-9370
Objective: HIV-1 is typically categorized by genetically distinct viral subtypes. Viral subtypes are usually compartmentalized by ethnicity and transmission group and, thus, convey important epidemiological information, as well as possibly influencing the rate of disease progression. We aim to describe the prevalence and time trends of subtypes observed among key populations living with HIV-1 in the UK.Design: Analyses of reverse transcriptase and protease sequences generated from HIV-1-positive antiretroviral-naive patients as part of routine resistance testing between 2002 and 2010 in all public health and NHS laboratories in the UK.Methods: Subtype was assigned centrally using the SCUEAL algorithm. Subtyping results were combined with data from the UK Collaborative HIV Cohort Study and the UK HIV and AIDS Reporting System. Analyses adjusted for the number of national HIV-1 diagnoses made each year within demographic subgroups. Viral subtypes were described overall, over time and by demographic subgroup.Results: Subtype B diagnoses (39.9%) have remained stable since 2005, whereas subtype C diagnoses (34.3%) were found to decline in prevalence from 2004. Across most demographic subgroups, the prevalence of non-B non-C subtypes has increased over time, in particular novel recombinant forms (9.9%), subtype G (2.7%), and CRF01 AE (2.0%).Conclusion: HIV-1 subtypes are increasingly represented across all demographic subgroups and this could be evidence of sexual mixing. Between 2002 and 2010, the prevalence of novel recombinant forms has increased in all demographic subgroups. This increasing genetic diversity and the effect of subtype on disease progression may impact future HIV-1 treatment and prevention.
Cotten M, Watson SJ, Zumla AI, et al., 2014, Spread, circulation, and evolution of the Middle East respiratory syndrome coronavirus, mBio, Vol: 5, Pages: 1-11, ISSN: 2150-7511
The Middle East respiratory syndrome coronavirus (MERS-CoV) was first documented in the Kingdom of Saudi Arabia (KSA) in 2012 and, to date, has been identified in 180 cases with 43% mortality. In this study, we have determined the MERS-CoV evolutionary rate, documented genetic variants of the virus and their distribution throughout the Arabian peninsula, and identified the genome positions under positive selection, important features for monitoring adaptation of MERS-CoV to human transmission and for identifying the source of infections. Respiratory samples from confirmed KSA MERS cases from May to September 2013 were subjected to whole-genome deep sequencing, and 32 complete or partial sequences (20 were ≥99% complete, 7 were 50 to 94% complete, and 5 were 27 to 50% complete) were obtained, bringing the total available MERS-CoV genomic sequences to 65. An evolutionary rate of 1.12 × 10−3 substitutions per site per year (95% credible interval [95% CI], 8.76 × 10−4; 1.37 × 10−3) was estimated, bringing the time to most recent common ancestor to March 2012 (95% CI, December 2011; June 2012). Only one MERS-CoV codon, spike 1020, located in a domain required for cell entry, is under strong positive selection. Four KSA MERS-CoV phylogenetic clades were found, with 3 clades apparently no longer contributing to current cases. The size of the population infected with MERS-CoV showed a gradual increase to June 2013, followed by a decline, possibly due to increased surveillance and infection control measures combined with a basic reproduction number (R0) for the virus that is less than 1.
Gall A, Morris C, Kellam P, et al., 2014, Complete genome sequence of the WHO International standard for HIV-1 RNA determined by deep sequencing, Genome Announc, Vol: 2, ISSN: 2169-8287
The World Health Organization (WHO) International Standard for HIV-1 RNA nucleic acid assays was characterized by complete genome deep sequencing analysis. The entire coding sequence and flanking long terminal repeats (LTRs), including minority species, were assigned subtype B. This information will aid the design, development, and evaluation of HIV-1 RNA amplification assays.
Gall A, Morris C, Kellam P, et al., 2014, Complete genome sequence of the WHO International Standard for HIV-1 RNA determined by deep sequencing, Genome Announcements, Vol: 2
© 2014 Gall et al. The World Health Organization (WHO) International Standard for HIV-1 RNA nucleic acid assays was characterized by complete genome deep sequencing analysis. The entire coding sequence and flanking long terminal repeats (LTRs), including minority species, were assigned subtype B. This information will aid the design, development, and evaluation of HIV-1 RNA amplification assays.
Smith SE, Weston S, Kellam P, et al., 2014, IFITM proteins - cellular inhibitors of viral entry, Current Opinion in Virology, Vol: 4, Pages: 71-77, ISSN: 1879-6257
Interferon inducible transmembrane (IFITM) proteins are a recently discovered family of cellular anti-viral proteins that restrict the replication of a number of enveloped and non-enveloped viruses. IFITM proteins are located in the plasma membrane and endosomal membranes, the main portals of entry for many viruses. Biochemical and membrane fusion studies suggest IFITM proteins have the ability to inhibit viral entry, possibly by modulating the fluidity of cellular membranes. Here we discuss the IFITM proteins, recent work on their mode of action, and future directions for research.
Jones M, Dry IR, Frampton D, et al., 2014, RNA-seq analysis of host and viral gene expression highlights interaction between Varicella Zoster virus and Keratinocyte differentiation, PLoS Pathogens, Vol: 10, ISSN: 1553-7366
Varicella zoster virus (VZV) is the etiological agent of chickenpox and shingles, diseases characterized by epidermal skin blistering. Using a calcium-induced keratinocyte differentiation model we investigated the interaction between epidermal differentiation and VZV infection. RNA-seq analysis showed that VZV infection has a profound effect on differentiating keratinocytes, altering the normal process of epidermal gene expression to generate a signature that resembles patterns of gene expression seen in both heritable and acquired skin-blistering disorders. Further investigation by real-time PCR, protein analysis and electron microscopy revealed that VZV specifically reduced expression of specific suprabasal cytokeratins and desmosomal proteins, leading to disruption of epidermal structure and function. These changes were accompanied by an upregulation of kallikreins and serine proteases. Taken together VZV infection promotes blistering and desquamation of the epidermis, both of which are necessary to the viral spread and pathogenesis. At the same time, analysis of the viral transcriptome provided evidence that VZV gene expression was significantly increased following calcium treatment of keratinocytes. Using reporter viruses and immunohistochemistry we confirmed that VZV gene and protein expression in skin is linked with cellular differentiation. These studies highlight the intimate host-pathogen interaction following VZV infection of skin and provide insight into the mechanisms by which VZV remodels the epidermal environment to promote its own replication and spread.
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