bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pseudotyping Incompatibility between HIV-1 and Gibbon Ape Leukemia Virus Env Is Modulated by Vpu
Authors: Lucas Tiffany M. , Lyddon Terri D. , Cannon Paula M. , Johnson Marc C. 
Published: December 2009

ABSTRACT

The Env protein from gibbon ape leukemia virus (GaLV) has been shown to be incompatible with human immunodeficiency virus type 1 (HIV-1) in the production of infectious pseudotyped particles. This incompatibility has been mapped to the C-terminal cytoplasmic tail of GaLV Env. Surprisingly, we found that the HIV-1 accessory protein Vpu modulates this incompatibility. The infectivity of HIV-1 pseudotyped with murine leukemia virus (MLV) Env was not affected by Vpu. However, the infectivity of HIV-1 pseudotyped with an MLV Env with the cytoplasmic tail from GaLV Env (MLV/GaLV Env) was restricted 50- to 100-fold by Vpu. A Vpu mutant containing a scrambled membrane-spanning domain, Vpu
RD
, was still able to restrict MLV/GaLV Env, but mutation of the serine residues at positions 52 and 56 completely alleviated the restriction. Loss of infectivity appeared to be caused by reduced MLV/GaLV Env incorporation into viral particles. The mechanism of this downmodulation appears to be distinct from Vpu-mediated CD4 downmodulation because Vpu-expressing cells that failed to produce infectious HIV-1 particles nonetheless continued to display robust surface MLV/GaLV Env expression. In addition, if MLV and HIV-1 were simultaneously introduced into the same cells, only the HIV-1 particle infectivity was restricted by Vpu. Collectively, these data suggest that Vpu modulates the cellular distribution of MLV/GaLV Env, preventing its recruitment to HIV-1 budding sites.
Activation of Peroxisome Proliferator-Activated Receptor Gamma by Human Cytomegalovirus for
De Novo
Replication Impairs Migration and Invasiveness of Cytotrophoblasts from Early Placentas
Authors: Rauwel Benjamin , Mariamé Bernard , Martin Hélène , Nielsen Ronni , Allart Sophie , Pipy Bernard , Mandrup Susanne , Devignes Marie Dominique , Evain-Brion Danièle , Fournier Thierry , Davrinche Christian 
Published: December 2009

ABSTRACT

Human cytomegalovirus (HCMV) contributes to pathogenic processes in immunosuppressed individuals, in fetuses, and in neonates. In the present report, by using reporter gene activation assays and confocal microscopy in the presence of a specific antagonist, we show for the first time that HCMV infection induces peroxisome proliferator-activated receptor gamma (PPARγ) transcriptional activity in infected cells. We demonstrate that the PPARγ antagonist dramatically impairs virus production and that the major immediate-early promoter contains PPAR response elements able to bind PPARγ, as assessed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Due to the key role of PPARγ in placentation and its specific trophoblast expression within the human placenta, we then provided evidence that by activating PPARγ human cytomegalovirus dramatically impaired early human trophoblast migration and invasiveness, as assessed by using well-established
in vitro
models of invasive trophoblast, i.e., primary cultures of extravillous cytotrophoblasts (EVCT) isolated from first-trimester placentas and the EVCT-derived cell line HIPEC. Our data provide new clues to explain how early infection during pregnancy could impair implantation and placentation and therefore embryonic development.
Canine Distemper Viruses Expressing a Hemagglutinin without N-Glycans Lose Virulence but Retain Immunosuppression
Authors: Sawatsky Bevan , von Messling Veronika 
Published: December 2009

ABSTRACT
Paramyxovirus glycoproteins are posttranslationally modified by the addition of N-linked glycans, which are often necessary for correct folding, processing, and cell surface expression. To establish the contribution of N glycosylation to morbillivirus attachment (H) protein function and overall virulence, we first determined the use of the potential N-glycosylation sites in the canine distemper virus (CDV) H proteins. Biochemical characterization revealed that the three sites conserved in all strains were N glycosylated, whereas only two of the up to five additional sites present in wild-type strains are used. A wild-type virus with an H protein reproducing the vaccine strain N-glycosylation pattern remained lethal in ferrets but with a prolonged course of disease. In contrast, introduction of the vaccine H protein in the wild-type context resulted in complete attenuation. To further characterize the role of N glycosylation in CDV pathogenesis, the N-glycosylation sites of wild-type H proteins were successively deleted, including a nonstandard site, to ultimately generate a nonglycosylated H protein. Despite reduced expression levels, this protein remained fully functional. Recombinant viruses expressing N-glycan-deficient H proteins no longer caused disease, even though their immunosuppressive capacities were retained, indicating that reduced N glycosylation contributes to attenuation without affecting immunosuppression.
The Capsid Proteins of Aleutian Mink Disease Virus Activate Caspases and Are Specifically Cleaved during Infection
Authors: Cheng Fang , Chen Aaron Yun , Best Sonja M. , Bloom Marshall E. , Pintel David , Qiu Jianming 
Published: December 2009

ABSTRACT

Aleutian mink disease virus (AMDV) is currently the only known member of the genus
Amdovirus
in the family
Parvoviridae
. It is the etiological agent of Aleutian disease of mink. We have previously shown that a small protein with a molecular mass of approximately 26 kDa was present during AMDV infection and following transfection of capsid expression constructs (J. Qiu, F. Cheng, L. R. Burger, and D. Pintel, J. Virol. 80:654-662, 2006). In this study, we report that the capsid proteins were specifically cleaved at aspartic acid residue 420 (D420) during virus infection, resulting in the previously observed cleavage product. Mutation of a single amino acid residue at D420 abolished the specific cleavage. Expression of the capsid proteins alone in Crandell feline kidney (CrFK) cells reproduced the cleavage of the capsid proteins in virus infection. More importantly, capsid protein expression alone induced active caspases, of which caspase-10 was the most active. Active caspases, in turn, cleaved capsid proteins
in vivo
. Our results also showed that active caspase-7 specifically cleaved capsid proteins at D420
in vitro
. These results suggest that viral capsid proteins alone induce caspase activation, resulting in cleavage of capsid proteins. We also provide evidence that AMDV mutants resistant to caspase-mediated capsid cleavage increased virus production approximately 3- to 5-fold in CrFK cells compared to that produced from the parent virus AMDV-G at 37°C but not at 31.8°C. Collectively, our results indicate that caspase activity plays multiple roles in AMDV infection and that cleavage of the capsid proteins might have a role in regulating persistent infection of AMDV.
Rapid Dissociation of HIV-1 from Cultured Cells Severely Limits Infectivity Assays, Causes the Inactivation Ascribed to Entry Inhibitors, and Masks the Inherently High Level of Infectivity of Virions
Authors: Platt Emily J. , Kozak Susan L. , Durnin James P. , Hope Thomas J. , Kabat David 
Published: December 2009

ABSTRACT
By using immunofluorescence microscopy to observe and analyze freshly made HIV-1 virions adsorbed onto cells, we found that they are inherently highly infectious, rather than predominantly defective as previously suggested. Surprisingly, polycations enhance titers 20- to 30-fold by stabilizing adsorption and preventing a previously undescribed process of rapid dissociation, strongly implying that infectivity assays for many viruses are limited not only by inefficient virus diffusion onto cells but also by a postattachment race between entry and dissociation. This kinetic competition underlies inhibitory effects of CCR5 antagonists and explains why adaptive HIV-1 mutations overcome many cell entry limitations by accelerating entry.
Evidence for Multiple Recent Host Species Shifts among the Ranaviruses (FamilyIridoviridae)
Authors: Jancovich James K. , Bremont Michel , Touchman Jeffrey W. , Jacobs Bertram L. 
Published: December 2009

ABSTRACTMembers of the genusRanavirus(familyIridoviridae) have been recognized as major viral pathogens of cold-blooded vertebrates. Ranaviruses have been associated with amphibians, fish, and reptiles. At this time, the relationships between ranavirus species are still unclear. Previous studies suggested that ranaviruses from salamanders are more closely related to ranaviruses from fish than they are to ranaviruses from other amphibians, such as frogs. Therefore, to gain a better understanding of the relationships among ranavirus isolates, the genome of epizootic hematopoietic necrosis virus (EHNV), an Australian fish pathogen, was sequenced. Our findings suggest that the ancestral ranavirus was a fish virus and that several recent host shifts have taken place, with subsequent speciation of viruses in their new hosts. The data suggesting several recent host shifts among ranavirus species increase concern that these pathogens of cold-blooded vertebrates may have the capacity to cross numerous poikilothermic species barriers and the potential to cause devastating disease in their new hosts.
Serotype-Specific Structural Differences in the Protease-Cofactor Complexes of the Dengue Virus Family
Authors: Chandramouli Sumana , Joseph Jeremiah S. , Daudenarde Sophie , Gatchalian Jovylyn , Cornillez-Ty Cromwell , Kuhn Peter 
Published: December 2009

ABSTRACT
With an estimated 40% of the world population at risk, dengue poses a significant threat to human health, especially in tropical and subtropical regions. Preventative and curative efforts, such as vaccine development and drug discovery, face additional challenges due to the occurrence of four antigenically distinct serotypes of the causative dengue virus (DEN1 to -4). Complex immune responses resulting from repeat assaults by the different serotypes necessitate simultaneous targeting of all forms of the virus. One of the promising targets for drug development is the highly conserved two-component viral protease NS2B-NS3, which plays an essential role in viral replication by processing the viral precursor polyprotein into functional proteins. In this paper, we report the 2.1-Å crystal structure of the DEN1 NS2B hydrophilic core (residues 49 to 95) in complex with the NS3 protease domain (residues 1 to 186) carrying an internal deletion in the N terminus (residues 11 to 20). While the overall folds within the protease core are similar to those of DEN2 and DEN4 proteases, the conformation of the cofactor NS2B is dramatically different from those of other flaviviral apoprotease structures. The differences are especially apparent within its C-terminal region, implicated in substrate binding. The structure reveals for the first time serotype-specific structural elements in the dengue virus family, with the reported alternate conformation resulting from a unique metal-binding site within the DEN1 sequence. We also report the identification of a 10-residue stretch within NS3pro that separates the substrate-binding function from the catalytic turnover rate of the enzyme. Implications for broad-spectrum drug discovery are discussed.
Adenovirus Type 5 E1A and E6 Proteins of Low-Risk Cutaneous Beta-Human Papillomaviruses Suppress Cell Transformation through Interaction with FOXK1/K2 Transcription Factors
Authors: Komorek Jessica , Kuppuswamy Mohan , Subramanian T. , Vijayalingam S. , Lomonosova Elena , Zhao Ling-jun , Mymryk Joe S. , Schmitt Kimberly , Chinnadurai G. 
Published: January 2010

ABSTRACT
The adenovirus (Adv) oncoprotein E1A stimulates cell proliferation and inhibits differentiation. These activities are primarily linked to the N-terminal region (exon 1) of E1A, which interacts with multiple cellular protein complexes. The C terminus (exon 2) of E1A antagonizes these processes, mediated in part through interaction with C-terminal binding proteins 1 and 2 (CtBP1/2). To identify additional cellular E1A targets that are involved in the modulation of E1A C-terminus-mediated activities, we undertook tandem affinity purification of E1A-associated proteins. Through mass spectrometric analysis, we identified several known E1A-interacting proteins as well as novel E1A targets, such as the forkhead transcription factors, FOXK1/K2. We identified a Ser/Thr-containing sequence motif in E1A that mediated interaction with FOXK1/K2. We demonstrated that the E6 proteins of two beta-human papillomaviruses (HPV14 and HPV21) associated with epidermodysplasia verruciformis also interacted with FOXK1/K2 through a motif similar to that of E1A. The E1A mutants deficient in interaction with FOXK1/K2 induced enhanced cell proliferation and oncogenic transformation. The hypertransforming activity of the mutant E1A was suppressed by HPV21 E6. An E1A-E6 chimeric protein containing the Ser/Thr domain of the E6 protein in E1A interacted efficiently with FOXK1/K2 and inhibited cell transformation. Our results suggest that targeting FOXK1/K2 may be a common mechanism for certain beta-HPVs and Adv5. E1A exon 2 mutants deficient in interaction with the dual-specificity kinases DYRK1A/1B and their cofactor HAN11 also induced increased cell proliferation and transformation. Our results suggest that the E1A C-terminal region may suppress cell proliferation and oncogenic transformation through interaction with three different cellular protein complexes: FOXK1/K2, DYRK(1A/1B)/HAN11, and CtBP1/2.
Evolution of the HIV-1
env
Gene in the Rag2
−/−
γ
C
−/−
Humanized Mouse Model
Authors: Ince William L. , Zhang Liguo , Jiang Qi , Arrildt Kathryn , Su Lishan , Swanstrom Ronald 
Published: December 2009

ABSTRACT

Rag2
−/−
γ
C
−/−
mice transplanted with human hematopoietic stem cells (DKO-hu-HSC mice) mimic aspects of human infection with human immunodeficiency virus type 1 (HIV-1), including sustained viral replication and CD4
+
T-cell decline. However, the extent of HIV-1 evolution during long-term infection in these humanized mice, a key feature of the natural infection, has not been assessed fully. In this study, we examined the types of genotypic and phenotypic changes in the viral
env
gene that occur in the viral populations of DKO-hu-HSC mice infected with the CCR5-tropic isolate HIV-1
JRCSF
for up to 44 weeks. The mean rate of divergence of viral populations in mice was similar to that observed in a cohort of humans during a similar period of infection. Many amino acid substitutions were common across mice, including losses of N-linked glycosylation sites and substitutions in the CD4 binding site and in CD4-induced epitopes, indicating common selective pressures between mice. In addition,
env
variants evolved sensitivity to antibodies directed at V3, suggesting a more open conformation for Env. This phenotypic change was associated with increased CD4 binding efficiency and was attributed to specific amino acid substitutions. In one mouse,
env
variants emerged that exhibited a CXCR4-tropic phenotype. These sequences were compartmentalized in the mesenteric lymph node. In summary, viral populations in these mice exhibited dynamic behavior that included sequence evolution, compartmentalization, and the appearance of distinct phenotypic changes. Thus, humanized mice offer a useful model for studying evolutionary processes of HIV-1 in a complex host environment.
Naturally Occurring Human Monoclonal Antibodies Neutralize both 1918 and 2009 Pandemic Influenza A (H1N1) Viruses
Authors: Krause Jens C. , Tumpey Terrence M. , Huffman Chelsey J. , McGraw Patricia A. , Pearce Melissa B. , Tsibane Tshidi , Hai Rong , Basler Christopher F. , Crowe James E. 
Published: December 2009

ABSTRACTThe 2009 pandemic influenza A (H1N1) virus exhibits hemagglutinin protein sequence homology with the 1918 pandemic influenza virus. We found that human monoclonal antibodies recognized the Sa antigenic site on the head domains of both 1918 and 2009 hemagglutinins, a site that is hypervariable due to immune selection. These antibodies exhibited high potency against the 2009 virusin vitro, and one exerted a marked therapeutic effectin vivo.
Two Kinetic Patterns of Epitope-Specific CD8 T-Cell Responses following Murine Gammaherpesvirus 68 Infection
Authors: Freeman Michael L. , Lanzer Kathleen G. , Cookenham Tres , Peters Bjoern , Sidney John , Wu Ting-Ting , Sun Ren , Woodland David L. , Sette Alessandro , Blackman Marcia A. 
Published: January 2010

ABSTRACTMurine gammaherpesvirus 68 (γHV68) provides an important experimental model for understanding mechanisms of immune control of the latent human gammaherpesviruses. Antiviral CD8 T cells play a key role throughout three separate phases of the infection: clearance of lytic virus, control of the latency amplification stage, and prevention of reactivation of latently infected cells. Previous analyses have shown that T-cell responses to two well-characterized epitopes derived from ORF6 and ORF61 progress with distinct kinetics. ORF6487-specific cells predominate early in infection and then decline rapidly, whereas ORF61524-specific cells continue to expand through early latency, due to sustained epitope expression. However, the paucity of identified epitopes to this virus has limited our understanding of the overall complexities of CD8 T-cell immune control throughout infection. Here we screened 1,383 predicted H-2b-restricted peptides and identified 33 responses, of which 21 have not previously been reported. Kinetic analysis revealed a spectrum of T-cell responses based on the rapidity of their decline after the peak acute response that generally corresponded to the expression patterns of the two previously characterized epitopes. The slowly declining responses that were maintained during latency amplification proliferated more rapidly and underwent maturation of functional avidity over time. Furthermore, the kinetics of decline was accelerated following infection with a latency-null mutant virus. Overall, the data show that γHV68 infection elicits a highly heterogeneous CD8 T-cell response that segregates into two distinctive kinetic patterns controlled by differential epitope expression during the lytic and latency amplification stages of infection.
N-Linked Glycan at Residue 523 of Human Parainfluenza Virus Type 3 Hemagglutinin-Neuraminidase Masks a Second Receptor-Binding Site
Authors: Mishin Vasiliy P. , Watanabe Makiko , Taylor Garry , DeVincenzo John , Bose Michael , Portner Allen , Alymova Irina V. 
Published: January 2010

ABSTRACT

The hemagglutinin-neuraminidase (HN) glycoprotein plays a critical role in parainfluenza virus replication. We recently found that in addition to the catalytic binding site, HN of human parainfluenza virus type 1 (hPIV-1) may have a second receptor-binding site covered by an N-linked glycan at residue 173, which is near the region of the second receptor-binding site identified in Newcastle disease virus (NDV) HN (I. A. Alymova, G. Taylor, V. P. Mishin, M. Watanabe, K. G. Murti, K. Boyd, P. Chand, Y. S. Babu, and A. Portner, J. Virol.
82:
8400-8410, 2008). Sequence analysis and superposition of the NDV and hPIV-3 HN dimer structures revealed that, similar to what was seen in hPIV-1, the N-linked glycan at residue 523 on hPIV-3 HN may cover a second receptor-binding site. Removal of this N-linked glycosylation site by an Asn-to-Asp substitution at residue 523 (N523D) changed the spectrum of the mutant virus's receptor specificity, delayed its elution from both turkey and chicken red blood cells, reduced mutant sensitivity (by about half) to the selective HN inhibitor BCX 2855 in hemagglutination inhibition tests, and slowed its growth in LLC-MK
2
cells. The neuraminidase activity of the mutant and its sensitivity to BCX 2855 in neuraminidase inhibition assays did not change, indicating that the mutation did not affect the virus's catalytic-binding site and that all observed effects were caused by the exposure of the purported second receptor-binding site. Our data are consistent with the idea that, similar to the case for hPIV-1, the N-linked glycan shields a second receptor-binding site on hPIV-3 HN.
ON TWO CONJECTURES FOR CURVES ON K3 SURFACES
Authors: KNUTSEN ANDREAS LEOPOLD 
Published: December 2009

We prove that the gonality among the smooth curves in a complete linear system on a K3 surface is constant except for the Donagi–Morrison example. This was proved by Ciliberto and Pareschi under the additional condition that the linear system is ample. The constancy was originally conjectured by Harris and Mumford. As a consequence we prove that exceptional curves on K3 surfaces satisfy the Eisenbud–Lange–Martens–Schreyer conjecture and explicitly describe such curves. They turn out to be natural extensions of the Eisenbud–Lange–Martens–Schreyer examples of exceptional curves on K3 surfaces.
Hybrid Methods for Equilibrium Problems and Fixed Points Problems of a Countable Family of Relatively Nonexpansive Mappings in Banach Spaces
Authors: Plubtieng Somyot , Sriprad Wanna 
Published: December 2009

AbstractThe purpose of this paper is to introduce hybrid projection algorithms for finding a common element of the set of common fixed points of a countable family of relatively nonexpansive mappings and the set of solutions of an equilibrium problem in the framework of Banach spaces. Moreover, we apply our result to the problem of finding a common element of an equilibrium problem and the problem of finding a zero of a maximal monotone operator. Our result improve and extend the corresponding results announced by Takahashi and Zembayashi (2008 and 2009), and many others.
Meeting Report on the Second Targeted Tumor Therapies
Authors: Bachran Christopher , Fuchs Hendrik 
Published: January 2010

Abstract
This meeting report on the fourth Fabisch Symposium for Cancer Research and Molecular Biology describes the aims of the international meeting, the main topics of the presentations, and the highlights of the conference. The fourth Fabisch Symposium was the second on Targeted Tumor Therapies and held from April 1–3, 2009 in Berlin, Germany. The meeting focused on noncarrier-based targeted tumor therapies and their clinical application. The world's leading experts in this field presented the state of the art on tumor-specific targeting and tumor growth inhibition, drug design and production, and the description of innovative strategies for improved delivery. The topics concentrated on immunotoxins and other targeted toxins as anticancer drugs, thus providing a specialized meeting platform not existing elsewhere for these therapeutics. Although a number of innovative approaches on the avoidance of immune responses against highly effective toxins were presented, a notable conclusion of the meeting and direction for future research is the acute need to further reduce the immunogenicity of the targeted toxins, which hampers the efficacy of this group of therapeutics in clinical studies. The meeting successfully fostered plans for further research and cooperation between different groups to hopefully achieve advanced translational and clinical studies. Mol Cancer Ther; 9(1); 17–23