bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physiological Levels of Virion-Associated Human Immunodeficiency Virus Type 1 Envelope Induce Coreceptor-Dependent Calcium Flux
Authors: Melar Marta , Ott David E. , Hope Thomas J. 
Published: November 2006

ABSTRACTHuman immunodeficiency virus (HIV) entry into target cells requires the engagement of receptor and coreceptor by envelope glycoprotein (Env). Coreceptors CCR5 and CXCR4 are chemokine receptors that generate signals manifested as calcium fluxes in response to binding of the appropriate ligand. It has previously been shown that engagement of the coreceptors by HIV Env can also generate Ca2+fluxing. Since the sensitivity and therefore the physiological consequence of signaling activation in target cells is not well understood, we addressed it by using a microscopy-based approach to measure Ca2+levels in individual CD4+T cells in response to low Env concentrations. Monomeric Env subunit gp120 and virion-bound Env were able to activate a signaling cascade that is qualitatively different from the one induced by chemokines. Env-mediated Ca2+fluxing was coreceptor mediated, coreceptor specific, and CD4 dependent. Comparison of the observed virion-mediated Ca2+fluxing with the exact number of viral particles revealed that the viral threshold necessary for coreceptor activation of signaling in CD4+T cells was quite low, as few as two virions. These results indicate that the physiological levels of virion binding can activate signaling in CD4+T cells in vivo and therefore might contribute to HIV-induced pathogenesis.
Microglial Cell Line Established from Prion Protein-Overexpressing Mice Is Susceptible to Various Murine Prion Strains
Authors: Iwamaru Yoshifumi , Takenouchi Takato , Ogihara Kazumasa , Hoshino Megumi , Takata Masuhiro , Imamura Morikazu , Tagawa Yuichi , Hayashi-Kato Hiroko , Ushiki-Kaku Yuko , Shimizu Yoshihisa , Okada Hiroyuki , Shinagawa Morikazu , Kitani Hiroshi , Yokoyama Takashi 
Published: November 2006

ABSTRACT

Several lines of evidence suggest that microglia have important roles in the pathogenesis of prion diseases. Here, we establish a novel microglial cell line (MG20) from neonatal
tga20
mice that overexpress murine prion protein. After exposure to Chandler scrapie, we observed the replication and accumulation of disease-associated forms of the prion protein in MG20 cells up to the 15th passage. Furthermore, MG20 cells were susceptible to ME7, Obihiro scrapie, and bovine spongiform encephalopathy agents. Thus, MG20 cell lines persistently infected with various murine prion strains provide a useful model for the study of the pathogenesis of prion diseases.
A Single-Nucleotide Synonymous Mutation in the
gag
Gene Controlling Human Immunodeficiency Virus Type 1 Virion Production
Authors: Hamano Takaichi , Matsuo Kazuhiro , Hibi Yurina , Victoriano Ann Florence B. , Takahashi Naoko , Mabuchi Yosio , Soji Tsuyoshi , Irie Shinji , Sawanpanyalert Pathom , Yanai Hideki , Hara Takashi , Yamazaki Shudo , Yamamoto Naoki , Okamoto Takashi 
Published: November 2006

ABSTRACT

Viral factors as well as host ones play major roles in the disease progression of human immunodeficiency virus type 1 (HIV-1) infection. We have examined cytotoxic T-lymphocyte activity and HIV-1 DNA PCR results of 312 high-risk seronegative drug users in northern Thailand and identified four seronegative cases positive for both assays. Furthermore, we have identified a synonymous mutation in nucleotide position 75 of the
gag
p17 gene (A426G) of HIV-1 that belongs to the CRF01_AE virus circulating in Thailand. The replication-competent HIV-1 clone containing the A426G mutation demonstrated a dramatic reduction of virion production and perturbation of viral morphogenesis without affecting viral protein synthesis in cells.
The Cytomegalovirus Homolog of Interleukin-10 Requires Phosphatidylinositol 3-Kinase Activity for Inhibition of Cytokine Synthesis in Monocytes
Authors: Spencer Juliet V. 
Published: November 2006

ABSTRACTHuman cytomegalovirus (CMV) has evolved numerous strategies for evading host immune defenses, including piracy of cellular cytokines. A viral homolog of interleukin-10, designated cmvIL-10, binds to the cellular IL-10 receptor and effects potent immune suppression. The signaling pathways employed by cmvIL-10 were investigated, and the classic IL-10R/JAK1/Stat3 pathway was found to be activated in monocytes. However, inhibition of JAK1 had little effect on cmvIL-10-mediated suppression of tumor necrosis factor alpha (TNF-α) production. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway had a more significant impact on TNF-α levels but did not completely relieve the immune suppression, demonstrating that cmvIL-10 stimulates multiple signaling pathways to modulate cell function.
Amelioration of Influenza Virus Pathogenesis in Chickens Attributed to the Enhanced Interferon-Inducing Capacity of a Virus with a Truncated NS1 Gene
Authors: Cauthen Angela N. , Swayne David E. , Sekellick Margaret J. , Marcus Philip I. , Suarez David L. 
Published: November 2006

ABSTRACT

Avian influenza virus (AIV) A/turkey/Oregon/71-SEPRL (TK/OR/71-SEPRL) (H7N3) encodes a full-length NS1 protein and is a weak inducer of interferon (IFN). A variant, TK/OR/71-delNS1 (H7N3), produces a truncated NS1 protein and is a strong inducer of IFN. These otherwise genetically related variants differ 20-fold in their capacities to induce IFN in primary chicken embryo cells but are similar in their sensitivities to the action of IFN. Furthermore, the weak IFN-inducing strain actively suppresses IFN induction in cells that are otherwise programmed to produce it. These phenotypic differences are attributed to the enhanced IFN-inducing capacity that characterizes type A influenza virus strains that produce defective NS1 protein. The pathogenesis of these two variants was evaluated in 1-day-old and 4-week-old chickens. The cell tropisms of both viruses were similar. However, the lesions in chickens produced by the weak IFN inducer were more severe and differed somewhat in character from those observed for the strong IFN inducer. Differences in lesions included the nature of inflammation, the rate of resolution of the infection, and the extent of viral replication and/or virus dissemination. The amelioration of pathogenesis is attributed to the higher levels of IFN produced by the variant encoding the truncated NS1 protein and the antiviral state subsequently induced by that IFN. The high titer of virus observed in kidney tissue (≈10
9
50% embryo lethal doses/g) from 1-day-old chickens infected intravenously by the weak IFN-inducing strain is attributed to the capacity of chicken kidney cells to activate the hemagglutinin fusion peptide along with their unresponsiveness to inducers of IFN as measured in vitro. Thus, the IFN-inducing capacity of AIV appears to be a significant factor in regulating the pathogenesis, virulence, and viral transmission of AIV in chickens. This suggests that the IFN-inducing and IFN induction suppression phenotypes of AIV should be considered when characterizing strains of influenza virus.
Silencing of both β-TrCP1 and HOS (β-TrCP2) Is Required To Suppress Human Immunodeficiency Virus Type 1 Vpu-Mediated CD4 Down-Modulation
Authors: Butticaz Christophe , Michielin Olivier , Wyniger Josiane , Telenti Amalio , Rothenberger Sylvia 
Published: November 2006

ABSTRACT

The human immunodeficiency virus type 1 (HIV-1) Vpu protein interacts with CD4 within the endoplasmic reticula of infected cells and targets CD4 for degradation through interaction with β-TrCP1. Mammals possess a homologue of β-TrCP1, HOS, which is also named β-TrCP2. We show by coimmunoprecipitation experiments that β-TrCP2 binds Vpu and is able to induce CD4 down-modulation as efficiently as β-TrCP1. In two different cell lines, HeLa CD4
+
and Jurkat, Vpu-mediated CD4 down-modulation could not be reversed through the individual silencing of endogenous β-TrCP1 or β-TrCP2 but instead required the two genes to be silenced simultaneously.
E6AP-Dependent Degradation of DLG4/PSD95 by High-Risk Human Papillomavirus Type 18 E6 Protein
Authors: Handa Keisuke , Yugawa Takashi , Narisawa-Saito Mako , Ohno Shin-ichi , Fujita Masatoshi , Kiyono Tohru 
Published: November 2006

ABSTRACT

In most cervical cancers, DNAs of high-risk mucosotropic human papillomaviruses (HPVs), such as types 16 and 18, are maintained so as to express two viral proteins, E6 and E7, suggesting that they play important roles in carcinogenesis. The carboxy-terminal PDZ domain-binding motif of the E6 proteins is in fact essential for transformation of rodent cells and induction of hyperplasia in E6-transgenic mouse skin. To date, seven PDZ domain-containing proteins, including DLG1/hDLG, which is a human homologue of the
Drosophila
discs large tumor suppressor (Dlg), have been identified as targets of high-risk HPV E6 proteins. Here, we describe DLG4/PSD95, another human homologue of Dlg, as a novel E6 target. DLG4 was found to be expressed in normal human cells, including cervical keratinocytes, but only to a limited extent in both HPV-positive and HPV-negative cervical cancer cell lines. Expression of HPV18 E6 in HCK1T decreased DLG4 levels more strongly than did HPV16 E6, the carboxy-terminal motif of the proteins being critical for binding and degradation of DLG4 in vitro. DLG4 levels were restored by expression of either E6AP-specific short hairpin RNA or bovine papillomavirus type 1 E2 in HeLa but not CaSki or SiHa cells, reflecting downregulation of DLG4 mRNA as opposed to protein by an HPV-independent mechanism in HPV16-positive cancer lines. The tumorigenicity of CaSki cells was strongly inhibited by forced expression of DLG4, while growth in culture was not inhibited at all. These results suggest that DLG4 may function as a tumor suppressor in the development of HPV-associated cancers.
Functional p53 Signaling in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas: Implications for Therapy
Authors: Petre Christin E. , Sin Sang-Hoon , Dittmer Dirk P. 
Published: November 2006

ABSTRACT
The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is associated with Kaposi's sarcoma (KS) as well as primary effusion lymphomas (PEL). The expression of viral proteins capable of inactivating the p53 tumor suppressor protein has been implicated in KSHV oncogenesis. However, DNA-damaging drugs such as doxorubicin are clinically efficacious against PEL and KS, suggesting that p53 signaling remains intact despite the presence of KSHV. To investigate the functionality of p53 in PEL, we examined the response of a large number of PEL cell lines to doxorubicin. Two out of seven (29%) PEL cell lines harbored a mutant p53 allele (BCBL-1 and BCP-1) which led to doxorubicin resistance. In contrast, all other PEL containing wild-type p53 showed DNA damage-induced cell cycle arrest, p53 phosphorylation, and p53 target gene activation. These data imply that p53-mediated DNA damage signaling was intact. Supporting this finding, chemical inhibition of p53 signaling in PEL led to doxorubicin resistance, and chemical activation of p53 by the Hdm2 antagonist Nutlin-3 led to unimpaired induction of p53 target genes as well as growth inhibition and apoptosis.
Involvement of Hsp90 in Assembly and Nuclear Import of Influenza Virus RNA Polymerase Subunits
Authors: Naito Tadasuke , Momose Fumitaka , Kawaguchi Atsushi , Nagata Kyosuke 
Published: November 2006

ABSTRACT
Transcription
and replication of the influenza virus RNA genome occur in the nuclei
of infected cells through the viral RNA-dependent RNA polymerase
consisting of PB1, PB2, and PA. We previously identified a
host factor designated RAF-1 (RNA polymerase activating factor 1) that
stimulates viral RNA synthesis. RAF-1 is found to be identical to
Hsp90. Here, we examined the intracellular localization of Hsp90 and
viral RNA polymerase subunits and their molecular interaction. Hsp90
was found to interact with PB2 and PB1, and it was relocalized to the
nucleus upon viral infection. We found that the nuclear transport of
Hsp90 occurs in cells expressing PB2 alone. The nuclear transport of
Hsp90 was in parallel with that of the viral RNA polymerase binary
complexes, either PB1 and PB2 or PB1 and PA, as well as with that of
PB2 alone. Hsp90 also interacted with the binary RNA polymerase complex
PB1-PB2, and it was dissociated from the PB1-PB2 complex upon its
association with PA. Furthermore, Hsp90 could form a stable
PB1-PB2-Hsp90 complex prior to the formation of a ternary polymerase
complex by the assembly of PA in the infected cells. These results
suggest that Hsp90 is involved in the assembly and nuclear transport of
viral RNA polymerase subunits, possibly as a molecular chaperone for
the polymerase subunits prior to the formation of a mature ternary
polymerase
complex.
Adenovirus Infection Triggers a Rapid, MyD88-Regulated Transcriptome Response Critical to Acute-Phase and Adaptive Immune Responses In Vivo
Authors: Hartman Zachary C. , Kiang Anne , Everett Ruth S. , Serra Delila , Yang Xiao Y. , Clay Timothy M. , Amalfitano Andrea 
Published: November 2006

ABSTRACT
Nearly 50 years ago, the discovery of interferon prompted the notion that host cells innately respond to viral invasion. Since that time, technological advances have allowed this response to be extensively characterized and dissected in vitro. However, these advances have only recently been applied to highly complex, in vivo biological systems. To this end, we exploited high-titer adenovirus (Ad) vectors to globally investigate the innate immune response to nonenveloped viral infection in vivo. Our results indicated a potent cellular transcriptome response shortly after infection, with global assessments revealing significant dysregulation in ∼15% of the measured transcripts derived from Ad vector-transduced tissue. Bioinformatics-based transcriptome analysis revealed a complex innate response to Ad infection, with induction of proinflammatory responses (and suppression of metabolism and mitochondrial genes) akin to those observed when mice are challenged with lipopolysaccharide. Despite this commonality, there were many unique aspects of the Ad-dependent transcriptome response, including the upregulation of several RNA regulatory mechanisms and apoptosis-related pathways, accompanied by the suppression of lysosomal and endocytic genes. Our results also implicated the Toll-like receptors (TLRs) in these responses, prompting specific investigations into this pathway. By using MyD88KO mice, our results confirmed that Ad-induced dysregulation of five functionally related gene clusters are significantly dependent on this TLR adaptor gene. MyD88 deficiency also resulted in significantly diminished, although not abolished, adaptive and acute-phase immune responses to Ad, confirming the transcriptome data, as well as specifically identifying MyD88 as a significant Ad immunity amplifier and regulator in vivo.
Type-Specific Epitopes Targeted by Monoclonal Antibodies with Exceptionally Potent Neutralizing Activities for Selected Strains of Human Immunodeficiency Virus Type 1 Map to a Common Region of the V2 Domain of gp120 and Differ Only at Single Positions from the Clade B Consensus Sequence
Authors: Honnen W. J. , Krachmarov C. , Kayman S. C. , Gorny M. K. , Zolla-Pazner S. , Pinter A. 
Published: November 2006

ABSTRACTOnly a few monoclonal antibodies (MAbs) have been isolated that recognize conserved sites in human immunodeficiency virus type 1 (HIV-1) Env proteins and possess broad neutralizing activities. Other MAbs directed against targets in various domains of Env have been described that are strongly neutralizing, but they possess limited breadth. One such MAb, 2909, possesses a uniquely potent neutralizing activity specific for a quaternary epitope on SF162 Env that requires the presence of both the V2 and the V3 domains. We now show that replacement of the SF162 V3 sequence with consensus V3 sequences of multiple subtypes led to attenuated but still potent neutralization by 2909 and that the main determinants for the type specificity of 2909 reside in the V2 domain. A substitution at position 160 completely eliminated 2909 reactivity, and mutations at position 167 either attenuated or potentiated neutralization by this antibody. Different substitutions at the same positions in V2 were previously shown to introduce epitopes recognized by MAbs 10/76b and C108g and to allow potent neutralization by these MAbs. Two substitutions at key positions in the V2 domain of JR-FL Env also allowed potent expression of the 2909 epitope, and single substitutions in YU2 V2 were sufficient for expression of the 2909, C108g, and 10/76b epitopes. These results demonstrate that the minimal epitopes for 2909, C108g, and 10/76b differed from that of the clade B consensus sequence only at single positions and suggest that all three MAbs recognize distinct variants of a relatively conserved sequence in V2 that is a particularly sensitive mediator of HIV-1 neutralization.
Effect of Rotavirus Strain on the Murine Model of Biliary Atresia
Authors: Allen Steven R. , Jafri Mubeen , Donnelly Bryan , McNeal Monica , Witte David , Bezerra Jorge , Ward Richard , Tiao Gregory M. 
Published: November 2006

ABSTRACT
Biliary atresia is a devastating disorder of the newborn in which afflicted infants develop inflammation and fibrosis of the extrahepatic biliary tract, resulting in cirrhosis and end-stage liver disease. Infection with a virus is thought to be a contributing factor in the etiology of biliary atresia. In the murine model of biliary atresia, perinatal exposure to rhesus rotavirus (RRV) results in biliary epithelial cell infection causing bile duct obstruction. The purpose of this study was to determine if tropism for the biliary epithelial cell was unique to RRV. Newborn mice underwent intraperitoneal injection with five strains of rotavirus: RRV (simian), SA11-FM (simian/bovine), SA11-SM (simian), EDIM (murine), and Wa (human). RRV and SA11-FM caused clinical manifestations of bile duct obstruction and high mortality. SA11-SM caused clinical signs of hepatobiliary injury but the mortality was markedly reduced. EDIM and Wa caused no sign of hepatobiliary disease. The systemic and temporal distribution of viral protein and live virus varied according to the injected strain. Immunohistochemistry revealed that RRV and SA11-FM targeted the biliary epithelial cells. In contrast, SA11-SM was found in the liver but in not in the biliary epithelium. These results indicate that strain-specific characteristics dictate tropism for cells of hepatobiliary origin which in turn impact the ability to induce the murine model of biliary atresia.
PTP-H2 and PTP-H3 fromMicroplitis demolitorBracovirus Localize to Focal Adhesions and Are Antiphagocytic in Insect Immune Cells
Authors: Pruijssers Andrea J. , Strand Michael R. 
Published: November 2006

ABSTRACTViruses in the familyPolydnaviridaeare symbiotically associated with parasitoid wasps. Wasps inject polydnaviruses (PDVs) when laying an egg into their insect host, and expression of viral gene products causes several physiological alterations, including immunosuppression, that allow the wasp's progeny to develop. As with other PDVs, mostMicroplitis demolitorbracovirus (MdBV) genes are related variants that form gene families. The largest MdBV gene family includes 13 members that encode predicted proteins related to protein tyrosine phosphatases (PTPs). Sequence analysis during the present study indicated that five PTP family members (PTP-H2, -H3, -N1, and -N2) have fully conserved catalytic domains, whereas other family members exhibited replacements, deletions, or rearrangements of amino acids considered essential for tyrosine phosphatase activity. Expression studies indicated that most MdBV PTP genes are expressed in virus-infected host insects, with transcript abundance usually being highest in hemocytes. MdBV-infected hemocytes also exhibited higher levels of tyrosine phosphatase activity than noninfected hemocytes. We produced expression constructs for four of the most abundantly expressed PTP family members and conducted functional studies with hemocyte-likeDrosophilaS2 cells. These experiments suggested that recombinant PTP-H2 and PTP-H3 are functional tyrosine phosphatases whereas PTP-H1 and PTP-J1 are not. PTP-H2 and -H3 localized to focal adhesions in S2 cells, and coexpression with another MdBV gene product, Glc1.8, resulted in complete inhibition of phagocytosis.
Rhinovirus Activates Interleukin-8 Expression via a Src/p110β Phosphatidylinositol 3-Kinase/Akt Pathway in Human Airway Epithelial Cells
Authors: Bentley J. Kelley , Newcomb Dawn C. , Goldsmith Adam M. , Jia Yue , Sajjan Uma S. , Hershenson Marc B. 
Published: November 2006

ABSTRACT

Rhinovirus (RV) is responsible for the majority of common colds and triggers exacerbations of asthma and chronic obstructive lung disease. We have shown that RV serotype 39 (RV39) infection activates phosphatidylinositol 3 (PI 3)-kinase and the serine threonine kinase Akt minutes after infection and that the activation of PI 3-kinase and Akt is required for maximal interleukin-8 (IL-8) expression. Here, we further examine the contributions of Src and PI 3-kinase activation to RV-induced Akt activation and IL-8 expression. Confocal fluorescent microscopy of 16HBE14o− human bronchial epithelial cells showed rapid (10-min) colocalization of RV39 with Src, p85α PI 3-kinase, p110β PI 3-kinase, Akt and Cit-Akt-PH, a fluorescent Akt pleckstrin homology domain which binds PI(3,4,5)P
3
. The chemical Src inhibitor PP2 {4-amino-5-(4-chlorophenyl)-7-(
t
-butyl)pyrazolo [3,4-
d
]pyrimidine} and the PI 3-kinase inhibitor LY294002 each inhibited Akt phosphorylation and the colocalization of RV39 with Akt. Digoxigenin-tagged RV coprecipitated with a Crosstide kinase likely to be Akt, and inhibition of Src blocked kinase activity. Digoxigenin-tagged RV39 colocalized with the lipid raft marker ceramide. In 16HBE14o− and primary mucociliary differentiated human bronchial epithelial cells, inhibition of Src kinase activity with the Src family chemical inhibitor PP2, dominant-negative Src (K297R), and Src small interfering RNA (siRNA) each inhibited RV39-induced IL-8 expression. siRNA against p110β PI 3-kinase also inhibited IL-8 expression. These data demonstrate that, in the context of RV infection, Src and p110β PI 3-kinase are upstream activators of Akt and the IL-8 promoter and that RV colocalizes with Src, PI 3-kinase, and Akt in lipid rafts.