bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of the Toll-Like Receptor 9 Signaling Pathway in the Induction of Innate Immunity by Baculovirus
Authors: Abe Takayuki , Hemmi Hiroaki , Miyamoto Hironobu , Moriishi Kohji , Tamura Shinichi , Takaku Hiroshi , Akira Shizuo , Matsuura Yoshiharu 
Published: February 2005

ABSTRACTWe have previously shown that mice inoculated intranasally with a wild-type baculovirus (Autographa californicanuclear polyhedrosis virus [AcNPV]) are protected from a lethal challenge by influenza virus. However, the precise mechanism of induction of this protective immune response by the AcNPV treatment remained unclear. Here we show that AcNPV activates immune cells via the Toll-like receptor 9 (TLR9)/MyD88-dependent signaling pathway. The production of inflammatory cytokines was severely reduced in peritoneal macrophages (PECs) and splenic CD11c+dendritic cells (DCs) derived from mice deficient in MyD88 or TLR9 after cultivation with AcNPV. In contrast, a significant amount of alpha interferon (IFN-α) was still detectable in the PECs and DCs of these mice after stimulation with AcNPV, suggesting that a TLR9/MyD88-independent signaling pathway might also participate in the production of IFN-α by AcNPV. Since previous work showed that TLR9 ligands include bacterial DNA and certain oligonucleotides containing unmethylated CpG dinucleotides, we also examined the effect of baculoviral DNA on the induction of innate immunity. Transfection of the murine macrophage cell line RAW264.7 with baculoviral DNA resulted in the production of the inflammatory cytokine, while the removal of envelope glycoproteins from viral particles, UV irradiation of the virus, and pretreatment with purified baculovirus envelope proteins or endosomal maturation inhibitors diminished the induction of the immune response by AcNPV. Together, these results indicate that the internalization of viral DNA via membrane fusion mediated by the viral envelope glycoprotein, as well as endosomal maturation, which releases the viral genome into TLR9-expressing cellular compartments, is necessary for the induction of the innate immune response by AcNPV.
Interferon Induction and/or Production and Its Suppression by Influenza A Viruses
Authors: Marcus Philip I. , Rojek Jillian M. , Sekellick Margaret J. 
Published: February 2005

ABSTRACT
Developmentally aged chicken embryo cells which hyperproduce interferon (IFN) when induced were used to quantify IFN production and its suppression by eight strains of type A influenza viruses (AIV). Over 90% of the IFN-inducing or IFN induction-suppressing activity of AIV populations resided in noninfectious particles. The IFN-inducer moiety of AIV appears to preexist in, or be generated by, virions termed IFN-inducing particles (IFP) and was detectable under conditions in which a single molecule of double-stranded RNA introduced into a cell via endocytosis induced IFN, whereas single-stranded RNA did not. Some AIV strains suppressed IFN production, an activity that resided in a noninfectious virion termed an IFN induction-suppressing particle (ISP). The ISP phenotype was dominant over the IFP phenotype. Strains of AIV varied 100-fold in their capacity to induce IFN. AIV genetically compromised in NS1 expression induced about 20 times more IFN than NS1-competent parental strains. UV irradiation further enhanced the IFN-inducing capacity of AIV up to 100-fold, converting ISP into IFP and IFP into more efficient IFP. AIV is known to prevent IFN induction and/or production by expressing NS1 from a small UV target (gene NS). Evidence is presented for an additional downregulator of IFN production, identified as a large UV target postulated to consist of AIV polymerase genes PB1 + PB2 + PA, through the ensuing action of their cap-snatching endonuclease on pre-IFN-mRNA. The products of both the small and large UV targets act in concert to regulate IFN induction and/or production. Knowledge of the IFP/ISP phenotype may be useful in the development of attenuated AIV strains that maximally induce cytokines favorable to the immune response.
Synthetic Double-Stranded RNA Poly(I:C) Combined with Mucosal Vaccine Protects against Influenza Virus Infection
Authors: Ichinohe Takeshi , Watanabe Izumi , Ito Satoshi , Fujii Hideki , Moriyama Masami , Tamura Shin-ichi , Takahashi Hidehiro , Sawa Hirofumi , Chiba Joe , Kurata Takeshi , Sata Tetsutaro , Hasegawa Hideki 
Published: February 2005

ABSTRACTThe mucosal adjuvant effect of synthetic double-stranded RNA polyriboinosinic polyribocytidylic acid [poly(I:C)] against influenza virus was examined under intranasal coadministration with inactivated hemagglutinin (HA) vaccine in BALB/c mice and was shown to have a protective effect against both nasal-restricted infection and lethal lung infection. Intranasal administration of vaccine from PR8 (H1N1) with poly(I:C) induced a high anti-HA immunoglobulin A (IgA) response in the nasal wash and IgG antibody response in the serum, while vaccination without poly(I:C) induced little response. Intracerebral injection confirmed the safety of poly(I:C). In addition, we demonstrated that administration of poly(I:C) with either A/Beijing (H1N1) or A/Yamagata (H1N1) vaccine conferred complete protection against PR8 challenge in this mouse nasal infection model, suggesting that poly(I:C) possessed cross-protection ability against variant viruses. To investigate the mechanism of the protective effect of poly(I:C), mRNA levels of Toll-like receptors and cytokines were examined in the nasal-associated lymphoid tissue after vaccination or virus challenge. Intranasal administration of HA vaccine with poly(I:C) up-regulated expression of Toll-like receptor 3 and alpha/beta interferons as well as Th1- and Th2-related cytokines. We propose that poly(I:C) is a new effective intranasal adjuvant for influenza virus vaccine.
Multiclade Human Immunodeficiency Virus Type 1 Envelope Immunogens Elicit Broad Cellular and Humoral Immunity in Rhesus Monkeys
Authors: Seaman Michael S. , Xu Ling , Beaudry Kristin , Martin Kristi L. , Beddall Margaret H. , Miura Ayako , Sambor Anna , Chakrabarti Bimal K. , Huang Yue , Bailer Robert , Koup Richard A. , Mascola John R. , Nabel Gary J. , Letvin Norman L. 
Published: February 2005

ABSTRACT
The development of a human immunodeficiency virus type 1 (HIV-1) vaccine that elicits potent cellular and humoral immune responses recognizing divergent strains of HIV-1 will be critical for combating the global AIDS epidemic. The present studies were initiated to examine the magnitude and breadth of envelope (Env)-specific T-lymphocyte and antibody responses generated by vaccines containing either a single or multiple genetically distant HIV-1 Env immunogens. Rhesus monkeys were immunized with DNA prime-recombinant adenovirus boost vaccines encoding a Gag-Pol-Nef polyprotein in combination with either a single Env or a mixture of clade-A, clade-B, and clade-C Envs. Monkeys receiving the multiclade Env immunization developed robust immune responses to all vaccine antigens and, importantly, a greater breadth of Env recognition than monkeys immunized with vaccines including a single Env immunogen. All groups of vaccinated monkeys demonstrated equivalent immune protection following challenge with the pathogenic simian-human immunodeficiency virus 89.6P. These data suggest that a multicomponent vaccine encoding Env proteins from multiple clades of HIV-1 can generate broad Env-specific T-lymphocyte and antibody responses without antigenic interference. This study demonstrates that it is possible to generate protective immune responses by vaccination with genetically diverse isolates of HIV-1.
DNA Damage Sensors ATM, ATR, DNA-PKcs, and PARP-1 Are Dispensable for Human Immunodeficiency Virus Type 1 Integration
Authors: Ariumi Yasuo , Turelli Priscilla , Masutani Mitsuko , Trono Didier 
Published: February 2005

ABSTRACT
Integration of a DNA copy of the viral RNA genome is a crucial step in the life cycle of human immunodeficiency virus type 1 (HIV-1) and other retroviruses. While the virally encoded integrase is key to this process, cellular factors yet to be characterized are suspected to participate in its completion. DNA damage sensors such as ATM (ataxia-telangiectasia mutated), ATR (ATM- and Rad3-related), DNA-PK (DNA-dependent protein kinase), and PARP-1 [poly(ADP-ribose) polymerase 1] play central roles in responses to various forms of DNA injury and as such could facilitate HIV integration. To test this hypothesis, we examined the susceptibility to infection with wild-type HIV-1 and to transduction with a vesicular stomatitis virus G protein (VSV-G)-pseudotyped HIV-1-derived lentiviral vector of human cells stably expressing small interfering RNAs against ATM, ATR, and PARP-1. We found that integration normally occurred in these knockdown cells. Similarly, the VSV-G-pseudotyped HIV-1-based vector could effectively transduce ATM and PARP-1 knockout mouse cells as well as human cells deficient for DNA-PK. Finally, treatment of target cells with the ATM and ATR inhibitors caffeine and wortmannin was without effect in these infectivity assays. We conclude that the DNA repair enzymes ATM, ATR, DNA-PKcs, and PARP-1 are not essential for HIV-1 integration.
Evidence for a New Viral Late-Domain Core Sequence, FPIV, Necessary for Budding of a Paramyxovirus
Authors: Schmitt Anthony P. , Leser George P. , Morita Eiji , Sundquist Wesley I. , Lamb Robert A. 
Published: February 2005

ABSTRACT
Enveloped virus budding has been linked to both the ubiquitin-proteasome pathway and the vacuolar protein-sorting pathway of cells. We show here for the paramyxovirus SV5 that proteasome inhibitors and expression of dominant-negative VPS4(E228Q) ATPase blocks budding. The SV5 matrix (M) protein lacks previously defined late domains (e.g., P[T/S]AP, PPxY, YPDL) that recruit cellular factors. We identified a new motif for budding (core sequence FPIV) that can compensate functionally for lack of a PTAP late domain in budding human immunodeficiency virus type 1 virus-like particles (VLPs). Mutagenesis experiments suggest the more general sequence Ø-P-x-V. The proline residue was found to be critically important for function of this sequence, as substitution of this proline in the SV5 M protein resulted in poor budding of SV5 VLPs and failure of recombinant SV5 virus to replicate normally. Adaptation of mutant virus occurred rapidly, resulting in new proline residues elsewhere in the M protein. We hypothesize that these proline residues act to partially restore virus budding by generation of new motifs that act as suboptimal late domains.
Use of a Murine Cytomegalovirus K181-Derived Bacterial Artificial Chromosome as a Vaccine Vector for Immunocontraception
Authors: Redwood Alec J. , Messerle Martin , Harvey Nicole L. , Hardy Christopher M. , Koszinowski Ulrich H. , Lawson Malcolm A. , Shellam Geoffrey R. 
Published: February 2005

ABSTRACTCytomegaloviruses (CMVs) are members of theBetaherpesvirinaesubfamily of theHerpesviridae, and their properties of latency, large DNA size, gene redundancy, and ability to be cloned as bacterial artificial chromosomes (BACs) suggest their utility as vaccine vectors. While the K181 strain of murine CMV (MCMV) is widely used to study MCMV biology, a BAC clone of this virus had not previously been produced. We report here the construction of a BAC clone of the K181Perthstrain of MCMV. The in vivo and in vitro growth characteristics of virus derived from the K181 BAC were similar to those of wild-type K181. The utility of the K181 BAC as a method for the rapid production of vaccine vectors was assessed. A vaccine strain of BAC virus, expressing the self-fertility antigen, murine zona pellucida 3, was produced rapidly using standard bacterial genetics techniques and rendered female BALB/c mice infertile with a single intraperitoneal inoculation. In addition, attenuated vaccine strains lacking the open reading framesm07tom12exhibited no reduction in efficacy compared to the full-length vaccine strain. In conclusion, we describe the production of a K181-based BAC virus which behaved essentially as wild-type K181 and allowed the rapid production of effective viral vaccine vectors.
Estradiol Regulates Susceptibility following Primary Exposure to Genital Herpes Simplex Virus Type 2, while Progesterone Induces Inflammation
Authors: Gillgrass Amy E. , Fernandez Sherie A. , Rosenthal Kenneth L. , Kaushic Charu 
Published: February 2005

ABSTRACTWe report here that sex hormones modulate susceptibility to a sexually transmitted viral agent, herpes simplex virus type 2 (HSV-2), in a mouse model. Ovariectomized mice were administered either saline (control), estradiol (E2), progesterone (P4), or a combination of both estradiol and progesterone (E+P) and infected intravaginally with HSV-2. With an inoculation dose of 105PFU, the saline- and P4-treated mice were found to be highly susceptible to genital HSV-2 infection. Both groups had extensive pathology and high viral titers in vaginal secretions, and 100% of mice succumbed by day 4 postinfection. E2-treated mice were protected from HSV-2 infection at the same dose and did not display any vaginal pathology or viral shedding. There was a slow progression of genital pathology in the combination hormone-treated group, along with prolonged viral shedding; 80% of animals succumbed by day 13. With lower inoculation doses of 103and 102PFU, 50 and 100%, respectively, of the combination hormone-treated mice survived. Localization of HSV-2 infection showed extensive infection in the vaginal epithelium of P4- and saline-treated animals within 24 h of inoculation. E2-treated animals were clear of infection, while the E+P-treated group had focal infection at 24 h that had progressed extensively by day 3. Infection was accompanied by persistent inflammation and infiltration of neutrophils in the P4-treated group. An analysis of the genes in the vaginal tissue showed that inflammation in the P4-treated group correlated with local induction of chemokines and chemokine receptors that were absent in the E2-treated mice and in uninfected P4-treated mice. The results show that sex hormones regulate initiation of infection and immune responses to genital HSV-2 infection.
Protection against Genital Herpes Infection in Mice Immunized under Different Hormonal Conditions Correlates with Induction of Vagina-Associated Lymphoid Tissue
Authors: Gillgrass Amy E. , Tang Vera A. , Towarnicki Kate M. , Rosenthal Kenneth L. , Kaushic Charu 
Published: February 2005

ABSTRACTThe present study was undertaken to examine the effect of the hormonal environment on immunization with an attenuated strain of herpes simplex virus type 2 (HSV-2 TK−) and subsequent protection against challenge. Ovariectomized mice were administered saline (S; control), estradiol (E2), progesterone (P4), or a combination of estradiol and progesterone (E+P) and immunized intravaginally (IVAG) with HSV-2 TK−. Three weeks later, the immunized mice were challenged IVAG with wild-type HSV-2. Mice that were immunized following E treatment were not protected, whereas complete protection against the challenge was seen in mice from the S- and P4-treated groups. In the P4-treated group, 15% of mice developed chronic pathology following TK−immunization. Interestingly, about 40% of the E+P-treated mice were also protected. Upon examination of viral shedding in the vaginal secretions, it was clear that protection against challenge was dependent on the ability of the TK−virus to cause productive genital infection under different hormonal conditions. In the protected mice (the S and P groups and part of the E+P group), induced vagina-associated lymphoid tissues composed of CD11c+dendritic cells and CD3+and CD4+T cells were formed transiently in the vaginal lamina propria from day 2 to day 5 postchallenge. These aggregates were absent in the unprotected mice (the E group and part of the E+P group). Significant HSV-2-specific activation of lymphocytes was observed in the local draining lymph nodes of protected mice. This response was absent in the unprotected groups. High titers of gB-specific local immunoglobulin A (IgA) antibodies were present in the vaginal secretions of S- and P4-treated immunized mice following HSV-2 challenge. The S-treated group of mice also had high gB-specific IgG titers. These studies show that sex hormones modify the induction of protective immune responses following IVAG immunization.
Transfer of the Full-Length Dystrophin-Coding Sequence into Muscle Cells by a Dual High-Capacity Hybrid Viral Vector with Site-Specific Integration Ability
Authors: Gonçalves Manuel A. F. V. , van Nierop Gijsbert P. , Tijssen Marloes R. , Lefesvre Pierre , Knaän-Shanzer Shoshan , van der Velde Ietje , van Bekkum Dirk W. , Valerio Dinko , de Vries Antoine A. F. 
Published: February 2005

ABSTRACT

Duchenne muscular dystrophy (DMD) is caused by mutations in the
DMD
gene, making it a potential target for gene therapy. There is, however, a scarcity of vectors that can accommodate the 14-kb
DMD
cDNA and permanently genetically correct muscle tissue in vivo or proliferating myogenic progenitors in vitro for use in autologous transplantation. Here, a dual high-capacity adenovirus-adeno-associated virus (hcAd/AAV) vector with two full-length human dystrophin-coding sequences flanked by AAV integration-enhancing elements is presented. These vectors are generated from input linear monomeric DNA molecules consisting of the Ad origin of replication and packaging signal followed by the recently identified AAV DNA integration efficiency element (p5IEE), the transgene(s) of interest, and the AAV inverted terminal repeat (ITR). After infection of producer cells with a helper Ad vector, the Ad DNA replication machinery, in concert with the AAV ITR-dependent dimerization, leads to the assembly of vector genomes with a tail-to-tail configuration that are efficiently amplified and packaged into Ad capsids. These dual hcAd/AAV hybrid vectors were used to express the dystrophin-coding sequence in rat cardiomyocytes in vitro and to restore dystrophin synthesis in the muscle tissues of
mdx
mice in vivo. Introduction into human cells of chimeric genomes, which contain a structure reminiscent of AAV proviral DNA, resulted in AAV Rep-dependent targeted DNA integration into the
AAVS1
locus on chromosome 19. Dual hcAd/AAV hybrid vectors may thus be particularly useful to develop safe treatment modalities for diseases such as DMD that rely on efficient transfer and stable expression of large genes.
Role of selectins in the triggering, growth, and dissemination of T-lymphoma cells: implication of L-selectin in the growth of thymic lymphoma
Authors: Bélanger Simon D. , St-Pierre Yves 
Published: February 2005

AbstractWe previously showed that intercellular adhesion molecule-1 (ICAM-1) expression by the host is essential for lymphoma dissemination. Because selectins usually act in a coordinated fashion with ICAM-1 in the recruitment of circulating normal cells, we investigated their implication in lymphomagenesis and metastasis. Using selectin-deficient mice, we found that though the absence of E-, P-, or L-selectins did not affect the triggering of radiation-induced thymic lymphoma, the absence of L-selectin on lymphoma cells reduced their capacity to grow in the thymus. This defect, however, was overcome by altering the integrity of the L-selectin-mediated interactions in the thymus, as shown in L-selectin-deficient mice and by adoptive transfer experiments. We also found that lack of selectin expression by the host significantly delayed the dissemination of lymphomas to peripheral tissues. This resistance of selectin-deficient mice to lymphoma metastasis was dependent on the intrinsic properties of lymphoma cells because highly tumorigenic variants were insensitive to the absence of selectins. Observations that lymphoma cells disseminate with the same efficiency in normal and selectin-deficient mice suggest that selectins exert their influence at the posthoming stage of metastasis, as does ICAM-1. These results provide definitive evidence that selectins play a significant role at different steps of T-cell lymphoma development. (Blood. 2005;105:4800-4806)
Thrombopoietin enhances expression of vascular endothelial growth factor (VEGF) in primitive hematopoietic cells through induction of HIF-1α
Authors: Kirito Keita , Fox Norma , Komatsu Norio , Kaushansky Kenneth 
Published: February 2005

Abstract
Thrombopoietin (TPO), the primary regulator of thrombopoiesis, is also an important, nonredundant mediator of hematopoietic stem cell (HSC) development. For example, following transplantation, HSC expansion is approximately 15-fold more robust in normal than in Tpo-/- mice. Vascular endothelial growth factor (VEGF) also plays an important role in HSC development, where it acts in an intracellular autocrine fashion to promote cell survival. Thus, we tested the hypothesis that TPO affects the autocrine production of VEGF to account for its favorable effects on HSCs. We found that VEGF transcripts are reduced in purified sca-1+/c-kit+/Gr-1- marrow cells derived from Tpo-/- mice and that TPO induces VEGF transcripts in these primitive hematopoietic cells. Additional studies determined that TPO induces VEGF expression by increasing the level of its primary transcription factor, hypoxia-inducible factor 1α (HIF-1α), by enhancing its protein stability. Moreover, VEGF expression is important for the TPO effect on primitive hematopoietic cells because blockade of the VEGF receptor with a specific inhibitor substantially blunts TPO-induced growth of single sca-1+/c-kit+/Gr-1- marrow cells in serum-free cultures. Along with previous findings that TPO affects Hox transcription factors that regulate HSC proliferation, these data contribute to our growing understanding of the mechanisms by which a hormone can influence stem cell development.
Endothelial apoptosis induced by inhibition of integrins αvβ3 and αvβ5 involves ceramide metabolic pathways
Authors: Erdreich-Epstein Anat , Tran Linda B. , Cox Órla T. , Huang Elaine Y. , Laug Walter E. , Shimada Hiroyuki , Millard Melissa 
Published: February 2005

AbstractMatrix ligation of integrins αvβ3/αvβ5 is critical for endothelial survival and angiogenesis. We have previously shown that ceramide, a proapoptotic lipid second messenger, increases during endothelial anoikis (detachment-induced apoptosis). We now show that RGDfV, an integrin αvβ3/αvβ5 cyclic function-blocking peptide, increased ceramide and decreased sphingomyelin in human brain microvascular endothelial cells (HBMECs) plated on vitronectin, suggesting that sphingomyelin hydrolysis contributes to RGDfV-induced ceramide increase. Desipramine and imipramine, inhibitors of acid sphingomyelinase (ASMase), suppressed RGDfV-induced ceramide increase. Importantly, desipramine, imipramine, and a third ASMase inhibitor, SR33557, but not inhibitors of neutral sphingomyelinase, suppressed RGDfV-induced apoptosis, suggesting that ASMase was required for integrin-mediated apoptosis. Myriocin, an inhibitor of de novo ceramide synthesis, had no effect on RGDfV-induced HBMEC apoptosis. Interestingly, ASMase inhibitors also suppressed the RGDfV-induced loss of spreading on vitronectin. RGDfV induced a similar increase in ceramide and apoptosis in HBMECs on poly-l-lysine or vitronectin, although cells detached only from vitronectin, indicating that cell detachment was not required for RGDfV-induced apoptosis. Our results suggest involvement of ASMase and ceramide in endothelial apoptosis induced by inhibition of integrins αvβ3/αvβ5, and propose a novel molecular mechanism for the antiangiogenic effect of RGDfV.