bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV Infection Upregulates Caveolin 1 Expression To Restrict Virus Production
Authors: Lin Shanshan , Wang Xiao Mei , Nadeau Peter E. , Mergia Ayalew 
Published: July 2010

ABSTRACT
Caveolin 1 (Cav-1) is a major protein of a specific membrane lipid raft known as caveolae. Cav-1 interacts with the gp41 of the human immunodeficiency virus (HIV) envelope, but the role of Cav-1 in HIV replication and pathogenesis is not known. In this report, we demonstrate that HIV infection in primary human monocyte-derived macrophages (MDMs), THP-1 macrophages, and U87-CD4 cells results in a dramatic upregulation of Cav-1 expression mediated by HIV Tat. The activity of p53 is essential for Tat-induced Cav-1 expression, as our findings show enhanced phosphorylation of serine residues at amino acid positions 15 and 46 in the presence of Tat with a resulting Cav-1 upregulation. Furthermore, inhibition of p38 mitogen-activated protein kinase (MAPK) blocked phosphorylation of p53 in the presence of Tat. Infection studies of Cav-1-overexpressing cells reveal a significant reduction of HIV production. Taken together, these results suggest that HIV infection enhances the expression of Cav-1, which subsequently causes virus reduction, suggesting that Cav-1 may contribute to persistent infection in macrophages.
Evolutionary Dynamics and Temporal/Geographical Correlates of Recombination in the Human Enterovirus Echovirus Types 9, 11, and 30
Authors: McWilliam Leitch E. C. , Cabrerizo M. , Cardosa J. , Harvala H. , Ivanova O. E. , Kroes A. C. M. , Lukashev A. , Muir P. , Odoom J. , Roivainen M. , Susi P. , Trallero G. , Evans D. J. , Simmonds P. 
Published: July 2010

ABSTRACT

The relationship between virus evolution and recombination in species B human enteroviruses was investigated through large-scale genetic analysis of echovirus type 9 (E9) and E11 isolates (
n
= 85 and 116) from 16 European, African, and Asian countries between 1995 and 2008. Cluster 1 E9 isolates and genotype D5 and A E11 isolates showed evidence of frequent recombination between the VP1 and 3Dpol regions, the latter falling into 23 (E9) and 43 (E11) clades interspersed phylogenetically with 46 3Dpol clades of E30 and with those of other species B serotypes. Remarkably, only 2 of the 112 3Dpol clades were shared by more than one serotype (E11 and E30), demonstrating an extremely large and genetically heterogeneous recombination pool of species B nonstructural-region variants. The likelihood of recombination increased with geographical separation and time, and both were correlated with VP1 divergence, whose substitution rates allowed recombination half-lives of 1.3, 9.8, and 3.1 years, respectively, for E9, E11, and E30 to be calculated. These marked differences in recombination dynamics matched epidemiological patterns of periodic epidemic cycles of 2 to 3 (E9) and 5 to 6 (E30) years and the longer-term endemic pattern of E11 infections. Phylotemporal analysis using a Bayesian Markov chain Monte Carlo method, which placed recombination events within the evolutionary reconstruction of VP1, showed a close relationship with VP1 lineage expansion, with defined recombination events that correlated with their epidemiological periodicity. Whether recombination events contribute directly to changes in transmissibility that drive epidemic behavior or occur stochastically during periodic population bottlenecks is an unresolved issue vital to future understanding of enterovirus molecular epidemiology and pathogenesis.
Baculovirus
Per Os
Infectivity Factors Form a Complex on the Surface of Occlusion-Derived Virus
Authors: Peng Ke , van Oers Monique M. , Hu Zhihong , van Lent Jan W. M. , Vlak Just M. 
Published: July 2010

ABSTRACT

Five highly conserved
per os
infectivity factors, PIF1, PIF2, PIF3, PIF4, and P74, have been reported to be essential for oral infectivity of baculovirus occlusion-derived virus (ODV) in insect larvae. Three of these proteins, P74, PIF1, and PIF2, were thought to function in virus binding to insect midgut cells. In this paper evidence is provided that PIF1, PIF2, and PIF3 form a stable complex on the surface of ODV particles of the baculovirus
Autographa californica
multinucleocapsid nucleopolyhedrovirus (AcMNPV). The complex could withstand 2% SDS-5% β-mercaptoethanol with heating at 50°C for 5 min. The complex was not formed when any of the genes for PIF1, PIF2, or PIF3 was deleted, while reinsertion of these genes into AcMNPV restored the complex. Coimmunoprecipitation analysis independently confirmed the interactions of the three PIF proteins and revealed in addition that P74 is also associated with this complex. However, deletion of the
p74
gene did not affect formation of the PIF1-PIF2-PIF3 complex. Electron microscopy analysis showed that PIF1 and PIF2 are localized on the surface of the ODV with a scattered distribution. This distribution did not change for PIF1 or PIF2 when the gene for PIF2 or PIF1 protein was deleted. We propose that PIF1, PIF2, PIF3, and P74 form an evolutionarily conserved complex on the ODV surface, which has an essential function in the initial stages of baculovirus oral infection.
Characterization of the Alpha Interferon-Induced Postentry Block to HIV-1 Infection in Primary Human Macrophages and T Cells
Authors: Goujon Caroline , Malim Michael H. 
Published: July 2010

ABSTRACTType I interferon (IFN) inhibits virus replication by activating multiple antiviral mechanisms and pathways. It has long been recognized that alpha interferon (IFN-α) can potently block both early and late stages of HIV-1 replication. The mechanistic basis for the early block(s) to infection is unknown, as is the identity of the participating antiviral factor(s). Here, we define the effect(s) of IFN-α on HIV-1 infection of primary human macrophages and CD4+T cells, as well as several monocytic and T-cell lines. We demonstrate that IFN-α treatment of macrophages, THP-1 cells, and, to a lesser extent, primary CD4+T cells markedly inhibits infection, whereas the effects are minimal in CD4+T-cell lines. Virus entry is essentially unaffected by IFN-α, but substantial decreases (sometimes >99%) in nascent cDNA accumulation correlate closely with losses in infectivity. Interestingly, proteasome inhibitors rescue viral cDNA accumulation, revealing a link between the ubiquitin-proteasome system and IFN-α-induced viral restriction. We also found that diverse primate and nonprimate retroviruses were susceptible to suppression by IFN-α. Importantly, all the primary and immortalized cells used here are proficient at responding to IFN-α, as judged by the induced expression of numerous IFN-stimulated genes, includingPKRandOAS1, indicating that a general deficiency in IFN-α responsiveness does not underlie IFN-α's inability to elicit an antiviral state in CD4+T-cell lines. Rather, we speculate that IFN-α fails to induce antiretroviral factors in these cells and that comparative transcriptional profiling with responsive cells, such as macrophages, invokes a strategy for identifying new host-encoded antiviral effectors.
Interferons Accelerate Decay of Replication-Competent Nucleocapsids of Hepatitis B Virus
Authors: Xu Chunxiao , Guo Haitao , Pan Xiao-Ben , Mao Richeng , Yu Wenquan , Xu Xiaodong , Wei Lai , Chang Jinhong , Block Timothy M. , Guo Ju-Tao 
Published: July 2010

ABSTRACT

Alpha interferon (IFN-α) is an approved medication for chronic hepatitis B. Gamma interferon (IFN-γ) is a key mediator of host antiviral immunity against hepatitis B virus (HBV) infection
in vivo
. However, the molecular mechanism by which these antiviral cytokines suppress HBV replication remains elusive. Using an immortalized murine hepatocyte (AML12)-derived cell line supporting tetracycline-inducible HBV replication, we show in this report that both IFN-α and IFN-γ efficiently reduce the amount of intracellular HBV nucleocapsids. Furthermore, we provide evidence suggesting that the IFN-induced cellular antiviral response is able to distinguish and selectively accelerate the decay of HBV replication-competent nucleocapsids but not empty capsids in a proteasome-dependent manner. Our findings thus reveal a novel antiviral mechanism of IFNs and provide a basis for a better understanding of HBV pathobiology.
Viral Particles of Endogenous Betaretroviruses Are Released in the Sheep Uterus and Infect the Conceptus Trophectoderm in a Transspecies Embryo Transfer Model
Authors: Black Sarah G. , Arnaud Frederick , Burghardt Robert C. , Satterfield M. Carey , Fleming Jo-Ann G. W. , Long Charles R. , Hanna Carol , Murphy Lita , Biek Roman , Palmarini Massimo , Spencer Thomas E. 
Published: July 2010

ABSTRACT

The sheep genome contains multiple copies of endogenous betaretroviruses highly related to the exogenous and oncogenic jaagsiekte sheep retrovirus (JSRV). The endogenous JSRVs (enJSRVs) are abundantly expressed in the uterine luminal and glandular epithelia as well as in the conceptus trophectoderm and are essential for conceptus elongation and trophectoderm growth and development. Of note, enJSRVs are present in sheep and goats but not cattle. At least 5 of the 27 enJSRV loci cloned to date possess an intact genomic organization and are able to produce viral particles
in vitro
. In this study, we found that enJSRVs form viral particles that are released into the uterine lumen of sheep. In order to test the infectious potential of enJSRV particles in the uterus, we transferred bovine blastocysts into synchronized ovine recipients and allowed them to develop for 13 days. Analysis of microdissected trophectoderm of the bovine conceptuses revealed the presence of enJSRV RNA and, in some cases, DNA. Interestingly, we found that RNAs belonging to only the most recently integrated enJSRV loci were packaged into viral particles and transmitted to the trophectoderm. Collectively, these results support the hypothesis that intact enJSRV loci expressed in the uterine endometrial epithelia are shed into the uterine lumen and could potentially transduce the conceptus trophectoderm. The essential role played by enJSRVs in sheep reproductive biology could also be played by endometrium-derived viral particles that influence development and differentiation of the trophectoderm.
Immunization with Wild-Type or CD4-Binding-Defective HIV-1 Env Trimers Reduces Viremia Equivalently following Heterologous Challenge with Simian-Human Immunodeficiency Virus
Authors: Sundling Christopher , O'Dell Sijy , Douagi Iyadh , Forsell Mattias N. , Mörner Andreas , Loré Karin , Mascola John R. , Wyatt Richard T. , Karlsson Hedestam Gunilla B. 
Published: July 2010

ABSTRACT

We recently reported that rhesus macaques inoculated with CD4-binding-competent and CD4-binding-defective soluble YU2-derived HIV-1 envelope glycoprotein (Env) trimers in adjuvant generate comparable levels of Env-specific binding antibodies (Abs) and T cell responses. We also showed that Abs directed against the Env coreceptor binding site (CoRbs) were elicited only in animals immunized with CD4-binding-competent trimers and not in animals immunized with CD4-binding-defective trimers, indicating that a direct interaction between Env and CD4 occurs
in vivo
. To investigate both the overall consequences of
in vivo
Env-CD4 interactions and the elicitation of CoRbs-directed Abs for protection against heterologous simian-human immunodeficiency virus (SHIV) challenge, we exposed rhesus macaques immunized with CD4-binding-competent and CD4-binding-defective trimers to the CCR5-tropic SHIV-SF162P4 challenge virus. Compared to unvaccinated controls, all vaccinated animals displayed improved control of plasma viremia, independent of the presence or absence of CoRbs-directed Abs prior to challenge. Immunization resulted in plasma responses that neutralized the heterologous SHIV challenge stock
in vitro
, with similar neutralizing Ab titers elicited by the CD4-binding-competent and CD4-binding-defective trimers. The neutralizing responses against both the SHIV-SF162P4 stock and a recombinant virus pseudotyped with a cloned SHIV-SF162P4-derived Env were significantly boosted by the SHIV challenge. Collectively, these results suggest that the capacity of soluble Env trimers to interact with primate CD4
in vivo
and to stimulate the production of moderate titers of CoRbs-directed Abs did not influence the magnitude of the neutralizing Ab recall response after viral challenge or the subsequent control of viremia in this heterologous SHIV challenge model.
Reconstitution of CD4 T Cells in Bronchoalveolar Lavage Fluid after Initiation of Highly Active Antiretroviral Therapy
Authors: Knox Kenneth S. , Vinton Carol , Hage Chadi A. , Kohli Lisa M. , Twigg Homer L. , Klatt Nichole R. , Zwickl Beth , Waltz Jeffrey , Goldman Mitchell , Douek Daniel C. , Brenchley Jason M. 
Published: July 2010

ABSTRACT
The massive depletion of gastrointestinal-tract CD4 T cells is a hallmark of the acute phase of HIV infection. In contrast, the depletion of the lower-respiratory-tract mucosal CD4 T cells as measured in bronchoalveolar lavage (BAL) fluid is more moderate and similar to the depletion of CD4 T cells observed in peripheral blood (PB). To understand better the dynamics of disease pathogenesis and the potential for the reconstitution of CD4 T cells in the lung and PB following the administration of effective antiretroviral therapy, we studied cell-associated viral loads, CD4 T-cell frequencies, and phenotypic and functional profiles of antigen-specific CD4 T cells from BAL fluid and blood before and after the initiation of highly active antiretroviral therapy (HAART). The major findings to emerge were the following: (i) BAL CD4 T cells are not massively depleted or preferentially infected by HIV compared to levels for PB; (ii) BAL CD4 T cells reconstitute after the initiation of HAART, and their infection frequencies decrease; (iii) BAL CD4 T-cell reconstitution appears to occur via the local proliferation of resident BAL CD4 T cells rather than redistribution; and (iv) BAL CD4 T cells are more polyfunctional than CD4 T cells in blood, and their functional profile is relatively unchanged after the initiation of HAART. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might aid in the reconstitution of mucosal CD4 T cells.
Identification of Novel Mutations Responsible for Resistance to MK-2048, a Second-Generation HIV-1 Integrase Inhibitor
Authors: Bar-Magen Tamara , Sloan Richard D. , Donahue Daniel A. , Kuhl Björn D. , Zabeida Alexandra , Xu Hongtao , Oliveira Maureen , Hazuda Daria J. , Wainberg Mark A. 
Published: July 2010

ABSTRACT

MK-2048 represents a prototype second-generation integrase strand transfer inhibitor (INSTI) developed with the goal of retaining activity against viruses containing mutations associated with resistance to first-generation INSTIs, raltegravir (RAL) and elvitegravir (EVG). Here, we report the identification of mutations (G118R and E138K) which confer resistance to MK-2048 and not to RAL or EVG. These mutations were selected
in vitro
and confirmed by site-specific mutagenesis. G118R, which appeared first in cell culture, conferred low levels of resistance to MK-2048. G118R also reduced viral replication capacity to approximately 1% that of the isogenic wild-type (wt) virus. The subsequent selection of E138K partially restored replication capacity to ≈13% of wt levels and increased resistance to MK-2048 to ≈8-fold. Viruses containing G118R and E138K remained largely susceptible to both RAL and EVG, suggesting a unique interaction between this second-generation INSTI and the enzyme may be defined by these residues as a potential basis for the increased intrinsic affinity and longer “off” rate of MK-2048.
In silico
structural analysis suggests that the introduction of a positively charged arginine at position 118, near the catalytic amino acid 116, might decrease Mg
2+
binding, compromising enzyme function and thus leading to the significant reduction in both integration and viral replication capacity observed with these mutations.
Ectromelia Virus Inhibitor of Complement Enzymes Protects Intracellular Mature Virus and Infected Cells from Mouse Complement
Authors: Moulton Elizabeth A. , Bertram Paula , Chen Nanhai , Buller R. Mark L. , Atkinson John P. 
Published: July 2010

ABSTRACTPoxviruses produce complement regulatory proteins to subvert the host's immune response. Similar to the human pathogen variola virus, ectromelia virus has a limited host range and provides a mouse model where the virus and the host's immune response have coevolved. We previously demonstrated that multiple components (C3, C4, and factor B) of the classical and alternative pathways are required to survive ectromelia virus infection. Complement's role in the innate and adaptive immune responses likely drove the evolution of a virus-encoded virulence factor that regulates complement activation. In this study, we characterized the ectromelia virus inhibitor of complement enzymes (EMICE). Recombinant EMICE regulated complement activation on the surface of CHO cells, and it protected complement-sensitive intracellular mature virions (IMV) from neutralizationin vitro. It accomplished this by serving as a cofactor for the inactivation of C3b and C4b and by dissociating the catalytic domain of the classical pathway C3 convertase. Infected murine cells initiated synthesis of EMICE within 4 to 6 h postinoculation. The levels were sufficient in the supernatant to protect the IMV, upon release, from complement-mediated neutralization. EMICE on the surface of infected murine cells also reduced complement activation by the alternative pathway. In contrast, classical pathway activation by high-titer antibody overwhelmed EMICE's regulatory capacity. These results suggest that EMICE's role is early during infection when it counteracts the innate immune response. In summary, ectromelia virus produced EMICE within a few hours of an infection, and EMICE in turn decreased complement activation on IMV and infected cells.
Fixed Point Theory for Contractive Mappings Satisfying "Equation missing" -Maps in "Equation missing" -Metric Spaces
Authors: Shatanawi W 
Published: July 2010

AbstractWe prove some fixed point results for self-mapping "Equation missing" in a complete "Equation missing"-metric space "Equation missing" under some contractive conditions related to a nondecreasing map "Equation missing" with "Equation missing" for all "Equation missing". Also, we prove the uniqueness of such fixed point, as well as studying the "Equation missing"-continuity of such fixed point.
Poly(ADP-Ribose) Polymerase Inhibitor Induces Accelerated Senescence in Irradiated Breast Cancer Cells and Tumors
Authors: Efimova Elena V. , Mauceri Helena J. , Golden Daniel W. , Labay Edwardine , Bindokas Vytautas P. , Darga Thomas E. , Chakraborty Chaitali , Barreto-Andrade Juan Camilo , Crawley Clayton , Sutton Harold G. , Kron Stephen J. , Weichselbaum Ralph R. 
Published: July 2010

Abstract
Persistent DNA double-strand breaks (DSB) may determine the antitumor effects of ionizing radiation (IR) by inducing apoptosis, necrosis, mitotic catastrophe, or permanent growth arrest. IR induces rapid modification of megabase chromatin domains surrounding DSBs via poly-ADP-ribosylation, phosphorylation, acetylation, and protein assembly. The dynamics of these IR-induced foci (IRIF) have been implicated in DNA damage signaling and DNA repair. As an IRIF reporter, we tracked the relocalization of green fluorescent protein fused to a chromatin binding domain of the checkpoint adapter protein 53BP1 after IR of breast cancer cells and tumors. To block DSB repair in breast cancer cells and tumors, we targeted poly(ADP-ribose) polymerase (PARP) with ABT-888 (veliparib), one of several PARP inhibitors currently in clinical trials. PARP inhibition markedly enhanced IRIF persistence and increased breast cancer cell senescence both in vitro and in vivo, arguing for targeting IRIF resolution as a novel therapeutic strategy. Cancer Res; 70(15); 6277–82. ©2010 AACR.
miRNA-96 Suppresses KRAS and Functions as a Tumor Suppressor Gene in Pancreatic Cancer
Authors: Yu Shuangni , Lu Zhaohui , Liu Changzheng , Meng Yunxiao , Ma Yihui , Zhao Wugan , Liu Jianping , Yu Jia , Chen Jie 
Published: July 2010

Abstract
Therapeutic applications of microRNA (miRNA) in KRAS-driven pancreatic cancers might be valuable, but few studies have explored this area. Here, we report that miR-96 directly targets the KRAS oncogene and functions as a tumor-suppressing miRNA in pancreatic cancer cells. Ectopic expression of miR-96 through a synthetic miRNA precursor inhibited KRAS, dampened Akt signaling, and triggered apoptosis in cells. In human clinical specimens, miR-96 was downregulated or deleted where an association with KRAS elevations was observed. In vitro and in vivo assays established that miR-96 decreased cancer cell invasion and migration and slowed tumor growth in a manner associated with KRAS downregulation. Our findings identify miR-96 as a potent regulator of KRAS, which may provide a novel therapeutic strategy for treatment of pancreatic cancer and other KRAS-driven cancers. Cancer Res; 70(14); 6015–25. ©2010 AACR.
Phosphomimetic Mutants of Pigment Epithelium-Derived Factor with Enhanced Antiangiogenic Activity as Potent Anticancer Agents
Authors: Konson Alexander , Pradeep Sunila , Seger Rony 
Published: July 2010

Abstract
Pigment epithelium-derived factor (PEDF) is an endogenous inhibitor of angiogenesis and a promising anticancer agent capable of suppressing solid tumor growth in animal cancer models. We have previously shown that PEDF can be phosphorylated and that distinct phosphorylation states of this factor differentially regulate its physiologic function. Here, we report that phosphomimetic mutants of PEDF, which possess significantly increased antiangiogenic activity, are much more efficient than wild-type (WT) PEDF in inhibiting growth and neovascularization in MDA-MB-231 (breast cancer), HCT116 (colon cancer), and U87-MG (glioblastoma) xenograft models. Importantly, the antitumor activity of the phosphomimetic mutants is comparable with that of the established antiangiogenic agent bevacizumab. However, unlike bevacizumab, these compounds act in a vascular endothelial growth factor (VEGF)–independent manner, as they do not affect the levels of VEGF-A mRNA and VEGF receptor 2 phosphorylation. Further immunohistochemical analysis revealed that PEDF mutants affect mainly tumor-residing endothelial cells and prevent the formation of intratumoral vascular network by facilitating endothelial cell apoptosis. It was also found that PEDF mutants reduce survival of endothelial cells in culture much better than WT-PEDF, an effect that is apparent even in the presence of VEGF or basic fibroblast growth factor, and promote much stronger endothelial cell apoptosis. On the other hand, PEDF and its mutants did not affect survival of cultured cancer cells, indicating that the antiangiogenic activity of these agents is the foremost element of the observed antitumor effect. These findings have specific implications on improving the properties of WT-PEDF, which is currently in preclinical development, and encourage the development of PEDF mutants as specific, neovascularization-targeting anticancer agents. Cancer Res; 70(15); 6247–57. ©2010 AACR.