bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fatal Subacute Myocarditis Associated with Human Bocavirus 2 in a 13-Month-Old Child
Authors: Brebion Amélie , Vanlieferinghen Philippe , Déchelotte Pierre , Boutry Morgane , Peigue-Lafeuille Hélène , Henquell Cécile 
Published: December 2013

ABSTRACT
Human bocavirus has rarely been incriminated in fatal or life-threatening respiratory infections. We report a case of fatal disseminated infection with subacute lymphocytic myocarditis in a 13-month-old child. The human bocavirus 2 genome was detected by PCR analysis in nasal swab, plasma, urine, ascitic fluid, and mesenteric node, skeletal muscle, and lung tissue specimens.
Controlled Clinical Comparison of BacT/Alert FA Plus and FN Plus Blood Culture Media with BacT/Alert FA and FN Blood Culture Media
Authors: Kirn T. J. , Mirrett S. , Reller L. B. , Weinstein M. P. 
Published: December 2013

ABSTRACT

New blood culture media containing antibiotic-binding polymeric beads have been developed for the BacT/Alert (bioMérieux, Inc., Durham, NC) blood culture system. To assess the performance of these new media, we compared the new BacT/Alert aerobic medium (FA Plus) with resins to BacT/Alert FA medium with activated charcoal and the new BacT/Alert anaerobic medium (FN Plus) to BacT/Alert FN medium at 3 tertiary care medical centers. Study bottle pairs were inoculated with a target volume of 6 to 10 ml of blood from adults and incubated in the BacT/Alert 3D blood culture instrument. In the FA Plus versus FA comparison, there were 1,507 study pairs. Among 170 isolates causing true bloodstream infections (BSIs), significantly more
Staphylococcus aureus
(
P
< 0.001) and total microorganisms (
P
< 0.01) grew in the FA Plus bottle than in the FA bottle. Fewer coagulase-negative staphylococcal (CoNS) contaminants grew in the FA Plus bottle than in the FA bottle (10 versus 22;
P
= 0.05). In addition, growth was detected earlier in the FA Plus bottle than in the FA bottle (
P
< 0.001). In the FN Plus versus FN comparison, there were 2,386 study pairs. Among 201 isolates causing true BSIs, significantly more
S. aureus
(
P
< 0.001), CoNS (
P
< 0.005), and total microorganisms (
P
< 0.001) grew in the FN Plus bottle than in the FN bottle. Also, significantly more CoNS contaminants grew in the FN Plus bottle than in the FN bottle (
P
< 0.001). Overall, microorganisms were detected earlier in the FN Plus than in the FN bottle (
P
< 0.001). Medical technologists at all 3 study sites preferred the new media for Gram stain interpretation. We conclude that the FA Plus and FN Plus media provide improved and earlier detection of microorganisms compared with the FA and FN media and are preferable for Gram stain interpretation as well.
Limited HIV-1 Superinfection in Seroconverters from the CAPRISA 004 Microbicide Trial
Authors: Redd Andrew D. , Mullis Caroline E. , Wendel Sarah K. , Sheward Daniel , Martens Craig , Bruno Daniel , Werner Lise , Garrett Nigel J. , Abdool Karim Quarraisha , Williamson Carolyn , Porcella Stephen F. , Quinn Thomas C. , Abdool Karim Salim S. 
Published: December 2013

ABSTRACT

HIV-1 superinfection (SI) occurs when an infected individual acquires a distinct new viral strain. The rate of superinfection may be reflective of the underlying HIV risk in a population. The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 clinical trial demonstrated that women who used a tenofovir-containing microbicide gel had lower rates of HIV infection than women using a placebo gel. Women who contracted HIV-1 during the trial were screened for the occurrence of superinfection by next-generation sequencing of the viral
gag
and
env
genes. There were two cases (one in each trial arm) of subtype C superinfection identified from the 76 women with primary infection screened at two time points (rate of superinfection, 1.5/100 person-years). Both women experienced a >0.5-log increase in viral load during the window when superinfection occurred. The rate of superinfection was significantly lower than the overall primary HIV incidence in the microbicide trial (incidence rate ratio [IRR], 0.20;
P
= 0.003). The women who seroconverted during the trial reported a significant increase in sexual contact with their stable partner 4 months after seroconversion (
P
< 0.001), which may have lowered the risk of superinfection in this population. The lower frequency of SI compared to the primary incidence is in contrast to a report from a general heterosexual African population but agrees with a study of high-risk women in Kenya. A better understanding of the rate of HIV superinfection could have important implications for ongoing HIV vaccine research.
H1N1, but Not H3N2, Influenza A Virus Infection Protects Ferrets from H5N1 Encephalitis
Authors: Bissel Stephanie J. , Wang Guoji , Carter Donald M. , Crevar Corey J. , Ross Ted M. , Wiley Clayton A. 
Published: December 2013

ABSTRACT
Seasonal influenza causes substantial morbidity and mortality because of efficient human-to-human spread. Rarely, zoonotic strains of influenza virus spread to humans, where they have the potential to mediate new pandemics with high mortality. We studied systemic viral spread after intranasal infection with highly pathogenic avian influenza virus (H5N1 [A/Viet Nam/1203/2004]) in ferrets with or without prior pandemic H1N1pdm09 (A/Mexico/4108/2009) or H3N2 (A/Victoria/361/2011) infection. After intranasal challenge with H5N1 influenza virus, naive ferrets rapidly succumbed to systemic infection. Animals challenged with H5N1 influenza virus greater than 3 months after recovering from an initial H1N1pdm09 infection survived H5N1 virus challenge and cleared virus from the respiratory tract 4 days after infection. However, a prolonged low-level infection of hematopoietic elements in the small bowel lamina propria, liver, and spleen was present for greater than 2 weeks postinfection, raising the potential for reassortment of influenza genes in a host infected with multiple strains of influenza. Animals previously infected with an H3N2 influenza virus succumbed to systemic disease and encephalitis after H5N1 virus challenge. These results indicate prior infection with different seasonal influenza strains leads to radically different protection from H5N1 challenge and fatal encephalitis.

IMPORTANCE
Seasonal influenza is efficiently transmitted from human to human, causing substantial morbidity and mortality. Rarely, zoonotic strains of influenza virus spread to humans, where they have the potential to mediate new pandemics with high mortality. Infection of naive ferrets with H5N1 avian influenza virus causes a rapid and lethal systemic disease. We studied systemic H5N1 viral spread after infection of ferrets with or without prior exposure to either of two seasonal influenza virus strains, H1N1 and H3N2. Ferrets previously infected with H1N1 survive H5N1 challenge while those previously infected with H3N2 die of encephalitis. However ferrets protected from lethal H5N1 infection develop persistent low-level infection of the small intestine, liver, or spleen, providing a nidus for future viral strain recombination. The mechanism by which prior infection with specific strains of seasonal influenza virus protect from lethal H5N1 challenge needs to be elucidated in order to design effective immunization and treatments.
Determining the Breadth of the Respiratory Syncytial Virus-Specific T Cell Response
Authors: McDermott Daniel S. , Knudson Cory J. , Varga Steven M. 
Published: December 2013

ABSTRACTRespiratory syncytial virus (RSV) is the most common cause of viral lower respiratory tract infections in infants and children under the age of 5. Studies examining RSV infection in susceptible BALB/c mice indicate that both CD4 and CD8 T cells not only contribute to viral clearance but also facilitate RSV-induced disease. However, efforts to understand the mechanisms by which RSV-specific T cells mediate disease following acute RSV infection have been hampered by the lack of defined RSV-specific T cell epitopes. Using an overlapping peptide library spanning each of the RSV-derived proteins, intracellular cytokine staining for gamma interferon was utilized to identify novel RSV-specific CD4 and CD8 T cell epitopes. Five novel CD8 T cell epitopes were revealed within the RSV fusion (F) protein and glycoprotein (G). In addition, five previously unidentified CD4 T cell epitopes were discovered, including epitopes in the phosphoprotein (P), polymerase protein (L), M2-1 protein, and nucleoprotein (N). Though the initial CD4 T cell epitopes were 15 amino acids in length, synthesis of longer peptides increased the frequency of responding CD4 T cells. Our results indicate that CD4 T cell epitopes that are 17 amino acids in length result in more optimal CD4 T cell stimulation than the commonly used 15-mer peptides.IMPORTANCERespiratory syncytial virus (RSV) is the leading cause of hospitalization for lower respiratory tract infection in children. T cells play a critical role in clearing an acute RSV infection, as well as contributing to RSV-induced disease. Here we examined the breadth of the RSV-specific T cell response, using for the first time an overlapping peptide library spanning the entire viral genome. We identified 5 new CD4 and 5 new CD8 T cell epitopes, including a CD8 T cell epitope within the G protein that was previously believed not to elicit a CD8 T cell response. Importantly, we also demonstrated that the use of longer, 17-mer peptides elicits a higher frequency of responding CD4 T cells than the more commonly used 15-mer peptides. Our results demonstrate the breadth of the CD4 and CD8 T cell response to RSV and demonstrate the importance of using longer peptides when stimulating CD4 T cell responses.
Genomewide Analysis of Reassortment and Evolution of Human Influenza A(H3N2) Viruses Circulating between 1968 and 2011
Authors: Westgeest Kim B. , Russell Colin A. , Lin Xudong , Spronken Monique I. J. , Bestebroer Theo M. , Bahl Justin , van Beek Ruud , Skepner Eugene , Halpin Rebecca A. , de Jong Jan C. , Rimmelzwaan Guus F. , Osterhaus Albert D. M. E. , Smith Derek J. , Wentworth David E. , Fouchier Ron A. M. , de Graaf Miranda 
Published: December 2013

ABSTRACT
Influenza A(H3N2) viruses became widespread in humans during the 1968 H3N2 virus pandemic and have been a major cause of influenza epidemics ever since. These viruses evolve continuously by reassortment and genomic evolution. Antigenic drift is the cause for the need to update influenza vaccines frequently. Using two data sets that span the entire period of circulation of human influenza A(H3N2) viruses, it was shown that influenza A(H3N2) virus evolution can be mapped to 13 antigenic clusters. Here we analyzed the full genomes of 286 influenza A(H3N2) viruses from these two data sets to investigate the genomic evolution and reassortment patterns. Numerous reassortment events were found, scattered over the entire period of virus circulation, but most prominently in viruses circulating between 1991 and 1998. Some of these reassortment events persisted over time, and one of these coincided with an antigenic cluster transition. Furthermore, selection pressures and nucleotide and amino acid substitution rates of all proteins were studied, including those of the recently discovered PB1-N40, PA-X, PA-N155, and PA-N182 proteins. Rates of nucleotide and amino acid substitutions were most pronounced for the hemagglutinin, neuraminidase, and PB1-F2 proteins. Selection pressures were highest in hemagglutinin, neuraminidase, matrix 1, and nonstructural protein 1. This study of genotype in relation to antigenic phenotype throughout the period of circulation of human influenza A(H3N2) viruses leads to a better understanding of the evolution of these viruses.

IMPORTANCE
Each winter, influenza virus infects approximately 5 to 15% of the world's population, resulting in significant morbidity and mortality. Influenza A(H3N2) viruses evolve continuously by reassortment and genomic evolution. This leads to changes in antigenic recognition (antigenic drift) which make it necessary to update vaccines against influenza A(H3N2) viruses frequently. In this study, the relationship of genetic evolution to antigenic change spanning the entire period of A(H3N2) virus circulation was studied for the first time. The results presented in this study contribute to a better understanding of genetic evolution in correlation with antigenic evolution of influenza A(H3N2) viruses.
Enhanced Virulence of Sheep-Passaged Bovine Spongiform Encephalopathy Agent Is Revealed by Decreased Polymorphism Barriers in Prion Protein Conversion Studies
Authors: Priem Jan , Langeveld Jan P. M. , van Keulen Lucien J. M. , van Zijderveld Fred G. , Andreoletti Olivier , Bossers Alex 
Published: December 2013

ABSTRACT

Bovine spongiform encephalopathy (BSE) can be efficiently transmitted to small ruminants (sheep and goats) with certain prion protein (PrP) genotypes. Polymorphisms in PrP of both the host and donor influence the transmission efficiency of transmissible spongiform encephalopathies (TSEs) in general. These polymorphisms in PrP also modulate the PrP conversion underlying TSE agent replication. Here we demonstrate that single-round protein misfolding cyclic amplification (PMCA) can be used to assess species and polymorphism barriers at the molecular level. We assessed those within and between the ovine and bovine species
in vitro
using a variety of natural scrapie and experimentally generated cross-species BSE agents. These BSE agents include ovBSE-ARQ isolates (BSE derived from sheep having the ARQ/ARQ PrP genotype), and two unique BSE-derived variants: BSE passaged in VRQ/VRQ sheep and a cow BSE agent isolate generated by back-transmission of ovBSE-ARQ into its original host. PMCA allowed us to quantitatively determine PrP conversion profiles that correlated with known
in vivo
transmissibility and susceptibility in the two ruminant species in which strain-specific molecular signatures, like its molecular weight after protease digestion, were maintained. Furthermore, both BSE agent isolates from ARQ and VRQ sheep demonstrated a surprising transmission profile in which efficient transmissions to both sheep and bovine variants was combined. Finally, all data support the notion that ARQ-derived sheep BSE points to a significant increase in virulence compared to all other tested scrapie- and BSE-derived variants reflected by the increased conversion efficiencies of previously inefficient convertible PrP variants (including the so-called “resistant” sheep ARR variant).

IMPORTANCE
Prion diseases such as scrapie in sheep and goats, BSE in cattle, and Creutzfeldt-Jakob disease (CJD) in humans are fatal neurodegenerative diseases caused by prions. BSE is known to be transmissible to a variety of hosts, including sheep and humans. Based on the typical BSE agent strain signatures and epidemiological data, the occurrence of a novel variant of CJD in humans was linked to BSE occurrence in the United Kingdom. Measures, including genetic selection of sheep toward less susceptible PrP genotypes, have been implemented to lower the risk of BSE transmission into sheep, since the disease could potentially spread into a natural reservoir. In this study, we demonstrated using molecular PrP conversion studies that when BSE is first transmitted through sheep, the host range is modified significantly and the PrP converting potency increased, allowing the ovine BSE to transmit more efficiently than cow BSE into supposedly less susceptible hosts.
Inhibition of Poliovirus-Induced Cleavage of Cellular Protein PCBP2 Reduces the Levels of Viral RNA Replication
Authors: Chase Amanda J. , Daijogo Sarah , Semler Bert L. 
Published: December 2013

ABSTRACT
Due to their small genome size, picornaviruses must utilize host proteins to mediate cap-independent translation and viral RNA replication. The host RNA-binding protein poly(rC) binding protein 2 (PCBP2) is involved in both processes in poliovirus infected cells. It has been shown that the viral proteinase 3CD cleaves PCBP2 and contributes to viral translation inhibition. However, cleaved PCBP2 remains active in viral RNA replication. This would suggest that both cleaved and intact forms of PCBP2 have a role in the viral RNA replication cycle. The picornavirus genome must act as a template for both translation and RNA replication. However, a template that is actively being translated cannot function as a template for RNA replication, suggesting that there is a switch in template usage from translation to RNA replication. We demonstrate that the cleavage of PCBP2 by the poliovirus 3CD proteinase is a necessary step for efficient viral RNA replication and, as such, may be important for mediating a switch in template usage from translation to RNA replication.

IMPORTANCE
Poliovirus, like all positive-strand RNA viruses that replicate in the cytoplasm of eukaryotic cells, uses its genomic RNA as a template for both viral protein synthesis and RNA replication. Given that these processes cannot occur simultaneously on the same template, poliovirus has evolved a mechanism(s) to facilitate the switch from using templates for translation to using them for RNA synthesis. This study explores one possible scenario for how the virus alters the functions of a host cell RNA binding protein to mediate, in part, this important transition.
GS-8374, a Prototype Phosphonate-Containing Inhibitor of HIV-1 Protease, Effectively Inhibits Protease Mutants with Amino Acid Insertions
Authors: Grantz Šašková Klára , Kožíšek Milan , Stray Kirsten , de Jong Dorien , Řezáčová Pavlína , Brynda Jiří , van Maarseveen Noortje M. , Nijhuis Monique , Cihlář Tomáš , Konvalinka Jan 
Published: December 2013

ABSTRACT

Insertions in the protease (PR) region of human immunodeficiency virus (HIV) represent an interesting mechanism of antiviral resistance against HIV PR inhibitors (PIs). Here, we demonstrate the improved ability of a phosphonate-containing experimental HIV PI, GS-8374, relative to that of other PIs, to effectively inhibit patient-derived recombinant HIV strains bearing PR insertions and numerous other mutations. We correlate enzyme inhibition with the catalytic activities of corresponding recombinant PRs
in vitro
and provide a biochemical and structural analysis of the PR-inhibitor complex.
Adenoviral Delivery of Recombinant Hepatitis B Virus Expressing Foreign Antigenic Epitopes for Immunotherapy of Persistent Viral Infection
Authors: Wang Zhuo , Zhu Kai , Bai Weiya , Jia Baosen , Hu Hao , Zhou Dongming , Zhang Xiaoming , Zhang Xinxin , Xie Youhua , Bourgine Maryline Mancini , Michel Marie-Louise , Lan Ke , Deng Qiang 
Published: December 2013

ABSTRACT

We previously reported a proof-of-concept study for curing chronic hepatitis B virus (HBV) infection using a foreign-antigen recombinant HBV (rHBV) as a gene therapy vector. Targeted elimination of wild-type HBV (wtHBV)-infected cells could be achieved by functionally activating an
in situ
T-cell response against the foreign antigen. However, as chronic HBV infection spreads to all hepatocytes, specific targeting of virus-infected cells is thought to be less critical. It is also feared that rHBV may not induce active immunization in a setting resembling natural infection. For this immunotherapeutic approach to be practically viable, in the present study, we used a recombinant adenovirus (rAd) vector for rHBV delivery. The rAd vector allowed efficient transduction of wtHBV-producing HepG2 cells, with transferred rHBV undergoing dominant viral replication. Progeny rHBV virions proved to be infectious, as demonstrated in primary tupaia hepatocytes. These results greatly expanded the antiviral capacity of the replication-defective rAd/rHBV in wtHBV-infected liver tissue. With prior priming in the periphery, transduction with rAd/rHBV attracted a substantial influx of the foreign-antigen-specific T-effector cells into the liver. Despite the fully activated T-cell response, active expression of rHBV was observed for a prolonged time, which is essential for rHBV to achieve sustained expansion. In a mouse model of HBV persistence established by infection with a recombinant adeno-associated virus carrying the wtHBV genome, rAd/rHBV-based immunotherapy elicited a foreign-antigen-specific T-cell response that triggered effective viral clearance and subsequent seroconversion to HBV. It therefore represents an efficient strategy to overcome immune tolerance, thereby eliminating chronic HBV infection.

IMPORTANCE
Adenovirus-delivered rHBV activated a foreign-antigen-specific T-cell response that abrogated HBV persistence in a mouse model. Our study provides further evidence of the potential of foreign-antigen-based immunotherapy for the treatment of chronic HBV infection.
Antiviral Activity of Lambda Interferon in Chickens
Authors: Reuter Antje , Soubies Sebastien , Härtle Sonja , Schusser Benjamin , Kaspers Bernd , Staeheli Peter , Rubbenstroth Dennis 
Published: December 2013

ABSTRACT

Interferons (IFNs) are essential components of the antiviral defense system of vertebrates. In mammals, functional receptors for type III IFN (lambda interferon [IFN-λ]) are found mainly on epithelial cells, and IFN-λ was demonstrated to play a crucial role in limiting viral infections of mucosal surfaces. To determine whether IFN-λ plays a similar role in birds, we produced recombinant chicken IFN-λ (chIFN-λ) and we used the replication-competent retroviral RCAS vector system to generate mosaic-transgenic chicken embryos that constitutively express chIFN-λ. We could demonstrate that chIFN-λ markedly inhibited replication of various virus strains, including highly pathogenic influenza A viruses,
in ovo
and
in vivo
, as well as in epithelium-rich tissue and cell culture systems. In contrast, chicken fibroblasts responded poorly to chIFN-λ. When applied
in vivo
to 3-week-old chickens, recombinant chIFN-λ strongly induced the IFN-responsive Mx gene in epithelium-rich organs, such as lungs, tracheas, and intestinal tracts. Correspondingly, these organs were found to express high transcript levels of the putative chIFN-λ receptor alpha chain (chIL28RA) gene. Transfection of chicken fibroblasts with a chIL28RA expression construct rendered these cells responsive to chIFN-λ treatment, indicating that receptor expression determines cell type specificity of IFN-λ action in chickens. Surprisingly, mosaic-transgenic chickens perished soon after hatching, demonstrating a detrimental effect of constitutive chIFN-λ expression. Our data highlight fundamental similarities between the IFN-λ systems of mammals and birds and suggest that type III IFN might play a role in defending mucosal surfaces against viral intruders in most if not all vertebrates.