bluuebunny/crossref_metadata_2025_split huggingface dataset:
EBNA2 Interferes with the Germinal Center Phenotype by Downregulating BCL6 and TCL1 in Non-Hodgkin's Lymphoma Cells
Authors: Boccellato Francesco , Anastasiadou Eleni , Rosato Paola , Kempkes Bettina , Frati Luigi , Faggioni Alberto , Trivedi Pankaj 
Published: December 2006

ABSTRACT
Epstein-Barr virus (EBV)-negative diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma-derived cell lines infected in vitro with a recombinant EBV expressed type II/III latency. High expression of EBNA2 inversely correlated with expression of germinal center (GC)-associated genes, BCL6 and TCL1. The decreased expression of BCL6 appeared to be dose dependent, with almost complete abrogation in highly EBNA2-expressing clones. The role of EBNA2 in negative regulation of these genes was confirmed by transfection and in a hormone-inducible EBNA2 cell system. LMP1 transfection reduced expression of TCL1, but not of BCL6, in DLBCLs. The GC-associated gene repression was at the transcriptional level and CBF1 independent. A decrease in HLA-DR, surface immunoglobulin M, and class II transactivator expression and an increase in CCL3, a BCL6 repression target, was observed in EBNA2-expressing clones. Since BCL6 is indispensable for GC formation and somatic hypermutations (SHM), we suggest that the previously reported lack of SHM seen in EBNA2-expressing GC cells from infectious mononucleosis tonsils could be due to negative regulation of BCL6 by EBNA2. These findings suggest that EBNA2 interferes with the GC phenotype.
Deterministic, Compensatory Mutational Events in the Capsid of Foot-and-Mouth Disease Virus in Response to the Introduction of Mutations Found in Viruses from Persistent Infections
Authors: Mateo Roberto , Mateu Mauricio G. 
Published: December 2006

ABSTRACTThe evolution of foot-and-mouth disease virus (FMDV) (biological clone C-S8c1) in persistently infected cells led to the emergence of a variant (R100) that displayed increased virulence, reduced stability, and other modified phenotypic traits. Some mutations fixed in the R100 genome involved a cluster of highly conserved residues around the capsid pores that participate in interactions with each other and/or between capsid protomers. We have investigated phenotypic and genotypic changes that occurred when these replacements were introduced into the C-S8c1 capsid. The C3007V and M3014L mutations exerted no effect on plaque size or viral yield during lytic infections, or on virion stability, but led to a reduction in biological fitness; the D3009A mutation caused drastic reductions in plaque size and viability. Remarkably, competition of the C3007V mutant with the nonmutated virus invariably resulted in the fixation of the D3009A mutation in the C3007V capsid. In turn, the presence of the D3009A mutation invariably led to the fixation of the M3014L mutation. In both cases, two individually disadvantageous mutations led, together, to an increase in fitness, as the double mutants outcompeted the nonmutated genotype. The higher fitness of C3007V/D3009A was related to a faster multiplication rate. These observations provide evidence for a chain of linked, compensatory mutational events in a defined region of the FMDV capsid. Furthermore, they indicate that the clustering of unique amino acid replacements in viruses from persistent infections may also occur in cytolytic infections in response to changes caused by previous mutations without an involvement of the new mutations in the adaptation to a different environment.
Synergistic Attenuation of Vesicular Stomatitis Virus by Combination of Specific G Gene Truncations and N Gene Translocations
Authors: Clarke David K. , Nasar Farooq , Lee Margaret , Johnson J. Erik , Wright Kevin , Calderon Priscilla , Guo Min , Natuk Robert , Cooper David , Hendry R. Michael , Udem Stephen A. 
Published: December 2006

ABSTRACT

A variety of rational approaches to attenuate growth and virulence of vesicular stomatitis virus (VSV) have been described previously. These include gene shuffling, truncation of the cytoplasmic tail of the G protein, and generation of noncytopathic M gene mutants. When separately introduced into recombinant VSV (rVSV), these mutations gave rise to viruses distinguished from their “wild-type” progenitor by diminished reproductive capacity in cell culture and/or reduced cytopathology and decreased pathogenicity in vivo. However, histopathology data from an exploratory nonhuman primate neurovirulence study indicated that some of these attenuated viruses could still cause significant levels of neurological injury. In this study, additional attenuated rVSV variants were generated by combination of the above-named three distinct classes of mutation. The resulting combination mutants were characterized by plaque size and growth kinetics in cell culture, and virulence was assessed by determination of the intracranial (IC) 50% lethal dose (LD
50
) in mice. Compared to virus having only one type of attenuating mutation, all of the mutation combinations examined gave rise to virus with smaller plaque phenotypes, delayed growth kinetics, and 10- to 500-fold-lower peak titers in cell culture. A similar pattern of attenuation was also observed following IC inoculation of mice, where differences in LD
50
of many orders of magnitude between viruses containing one and two types of attenuating mutation were sometimes seen. The results show synergistic rather than cumulative increases in attenuation and demonstrate a new approach to the attenuation of VSV and possibly other viruses.
Histone Modification Pattern of the T-Cellular
Herpesvirus Saimiri
Genome in Latency
Authors: Alberter Barbara , Ensser Armin 
Published: December 2006

ABSTRACT

Herpesvirus saimiri
(HVS) subgroup C strains are able to growth transform human T lymphocytes in vitro. The stably persisting and nonintegrating HVS episome represents an optimal prerequisite for the investigation of the epigenetic state of latent herpesvirus genomes in vitro. Quantitative chromatin immunoprecipitation experiments using seven different histone acetylation- or methylation-specific antibodies revealed repressive marks at four lytic gene promoters and a variable pattern at the weakly transcribed LANA/
orf73
promoter. The constitutive
stpC/tip
promoter regulating the viral oncoproteins and, more interestingly, the noncoding repetitive H-DNA elements flanking the coding region, showed a permissive chromatin structure. This study provides an appropriate model for the analysis of epigenetic herpesvirus genome modifications and their dynamics in T cells.
CD4 Coexpression Regulates DC-SIGN-Mediated Transmission of Human Immunodeficiency Virus Type 1
Authors: Wang Jian-Hua , Janas Alicia M. , Olson Wendy J. , KewalRamani Vineet N. , Wu Li 
Published: December 2006

ABSTRACTDendritic cells (DCs) potently stimulate the cell-cell transmission of human immunodeficiency virus type 1 (HIV-1). However, the mechanisms that underlie DC transmission of HIV-1 to CD4+T cells are not fully understood. DC-SIGN, a C-type lectin, efficiently promotes HIV-1transinfection. DC-SIGN is expressed in monocyte-derived DCs (MDDCs), macrophage subsets, activated B lymphocytes, and various mucosal tissues. MDDC-mediated HIV-1 transmission to CD4+T cells involves DC-SIGN-dependent and -independent mechanisms. DC-SIGN transmission of HIV-1 depends on the donor cell type. HIV-1 Nef can upregulate DC-SIGN expression and promote DC-T-cell clustering and HIV-1 spread. Nef also downregulates CD4 expression; however, the effect of the CD4 downmodulation on DC-mediated HIV-1 transmission has not been examined. Here, we report that CD4 expression levels correlate with inefficient HIV-1 transmission by monocytic cells expressing DC-SIGN. Expression of CD4 on Raji B cells strongly impaired DC-SIGN-mediated HIV-1 transmission to T cells. By contrast, enhanced HIV-1 transmission was observed when CD4 molecules on MDDCs and DC-SIGN-CD4-expressing cell lines were blocked with specific antibodies. Coexpression of CD4 and DC-SIGN in Raji cells promoted the internalization and intracellular retention of HIV-1. Interestingly, internalized HIV-1 particles were sorted and confined to late endosomal compartments that were positive for CD63 and CD81. Furthermore, in HIV-1-infected MDDCs, significant downregulation of CD4 by Nef expression correlated with enhanced viral transmission. These results suggest that CD4, which is present at various levels in DC-SIGN-positive primary cells, is a key regulator of HIV-1 transmission.
Evolutionary Mechanisms of Persistence and Diversification of a Calicivirus within Endemically Infected Natural Host Populations
Authors: Coyne Karen P. , Gaskell Rosalind M. , Dawson Susan , Porter Carol J. , Radford Alan D. 
Published: December 2006

ABSTRACT

In order to understand the evolutionary mechanisms of persistence and diversification within the
Caliciviridae
, we have been exploiting endemic infection of feline calicivirus within five geographically distinct household groups of cats. By sequencing immunodominant and variable regions of the capsid gene, we identified the relative contribution of the different evolutionary processes employed by the virus to ensure its long-term survival in the host population. Such strategies included progressive evolution of a given variant of a strain through mutation accumulation within an individual, sequential reinfection with either a variant of the same strain or with a different strain, and mixed infection. Recombination between different strains in this study has been reported in detail elsewhere (K. P. Coyne et al., J. Gen. Virol.
87:
921-926, 2006). Here, we provide evidence to suggest that true long-term persistent infection in individuals is relatively rare, with the majority of apparent viral carriers undergoing a combination of progressive evolution and cyclical reinfection. Progressive evolution at the individual level and variant reinfection at both the individual and population levels were associated with positive selection. Two measures of evolution rate were determined; for a virus progressively evolving within an individual (1.32 × 10
−2
to 2.64 × 10
−2
substitutions per nucleotide per year, i.e., no transmission) and for a strain circulating within a population (3.84 × 10
−2
to 4.56 × 10
−2
substitutions per nucleotide per year, i.e., including transmission). Reiteration of both progressive evolution and variant reinfection appeared to lead to a gradual increase in the diversity of a given strain of virus, both in the individual and in the population, until eventually new strains emerged.
Monoclonal Antibodies to Phosphatidylinositol Phosphate Neutralize Human Immunodeficiency Virus Type 1: Role of Phosphate-Binding Subsites
Authors: Brown Bruce K. , Karasavvas Nicos , Beck Zoltan , Matyas Gary R. , Birx Deborah L. , Polonis Victoria R. , Alving Carl R. 
Published: December 2006

ABSTRACTBoth a murine monoclonal antibody to phosphatidylinositol phosphate (PIP) and a human monoclonal antibody (4E10) that is known to have broadly neutralizing capabilities against primary isolates of human immunodeficiency virus type 1 (HIV-1) bound to PIP, as determined by enzyme-linked immunosorbent assay. Each of the antibodies had antigen subsite binding specificities in aqueous medium for small phosphate-containing molecules and for inositol. The anti-PIP monoclonal antibody inhibited infection by two HIV-1 primary isolates in neutralization assays employing primary human peripheral blood mononuclear cells. The data suggest that PIP or related lipids having free phosphates could serve as targets for the neutralization of HIV-1.
Intracellular Tat of Human Immunodeficiency Virus Type 1 Activates Lytic Cycle Replication of Kaposi's Sarcoma-Associated Herpesvirus: Role of JAK/STAT Signaling
Authors: Zeng Yi , Zhang Xunhai , Huang Zan , Cheng Lin , Yao Shuihong , Qin Di , Chen Xiuying , Tang Qiao , Lv Zhigang , Zhang Ling , Lu Chun 
Published: December 2006

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) infection significantly increases the risk of Kaposi's sarcoma (KS) occurrence in individuals infected with Kaposi's sarcoma-associated herpesvirus (KSHV). KSHV infection appears to be necessary but not sufficient for KS development without other cofactors. However, factors that facilitate KSHV to cause KS have not been well defined. Previously, we determined that human herpesvirus 6 was one of the cofactors that activated lytic cycle replication of KSHV. Here, we demonstrate that the Tat protein of HIV-1 is a potentially important factor in the pathogenesis of KS, as determined by production of lytic phase mRNA transcripts and viral proteins in BCBL-1 cells. Mechanistic studies showed ectopic expression of Tat induced the production of human interleukin-6 (huIL-6) and its receptor (huIL-6Ra) and activated STAT3 signaling. Neutralization of huIL-6 or huIL-6R or inhibition of STAT3 signaling enhanced the replication. In addition, IL-4/STAT6 signaling also partially contributed to Tat-induced KSHV replication. These findings suggest that Tat may participate in KS pathogenesis by inducing KSHV replication and increasing KSHV viral load. These data also suggest that JAK/STAT signaling may be of therapeutic value in AIDS-related KS patients.
Herpes Simplex Virus Type 2 (HSV-2) Establishes Latent Infection in a Different Population of Ganglionic Neurons than HSV-1: Role of Latency-Associated Transcripts
Authors: Margolis Todd P. , Imai Yumi , Yang Li , Vallas Vicky , Krause Philip R. 
Published: December 2006

ABSTRACT
Herpes simplex virus type 1 (HSV-1) and HSV-2 cause very similar acute infections but differ in their abilities to reactivate from trigeminal and dorsal root ganglia. To investigate differences in patterns of viral infection, we colabeled murine sensory ganglia for evidence of HSV infection and for the sensory neuron marker A5 or KH10. During acute infection, 7 to 10% of HSV-1 or HSV-2 antigen-positive neurons were A5 positive and 13 to 16% were KH10 positive, suggesting that both viruses reach each type of neuron in a manner proportional to their representation in uninfected ganglia. In murine trigeminal ganglia harvested during HSV latency, 25% of HSV-1 latency-associated transcript (LAT)- and 4% of HSV-2 LAT-expressing neurons were A5 positive, while 12% of HSV-1 LAT- and 42% of HSV-2 LAT-expressing neurons were KH10 positive. A similar difference was observed in murine dorsal root ganglia. These differences could not be attributed to differences in LAT expression levels in A5- versus KH10-positive neurons. Thus, HSV-1 demonstrated a preference for the establishment of latency in A5-positive neurons, while HSV-2 demonstrated a preference for the establishment of latency in KH10-positive neurons. A chimeric HSV-2 mutant that expresses the HSV-1 LAT exhibited an HSV-1 phenotype, preferentially establishing latency in A5-positive neurons. These data imply that the HSV-1 and HSV-2 LAT regions influence the ability of virus to establish latency in different neuronal subtypes. That the same chimeric virus has a characteristic HSV-1 reactivation phenotype further suggests that LAT-influenced establishment of latency in specific neuronal subtypes could be an important part of the mechanism by which LAT influences viral reactivation phenotypes.
Isolation and Characterization of Replication-Competent Human Immunodeficiency Virus Type 1 from a Subset of Elite Suppressors
Authors: Blankson Joel N. , Bailey Justin R. , Thayil Seema , Yang Hung-Chih , Lassen Kara , Lai Jun , Gandhi Shiv K. , Siliciano Janet D. , Williams Thomas M. , Siliciano Robert F. 
Published: December 2006

ABSTRACT
Elite suppressors (ES) are untreated human immunodeficiency virus type 1 (HIV-1)-infected individuals who control viremia to levels below the limit of detection of current assays. The mechanisms involved in this control have not been fully elucidated. Several studies have demonstrated that some ES are infected with defective viruses, but it remains unclear whether others are infected with replication-competent HIV-1. To answer this question, we used a sensitive coculture assay in an attempt to isolate replication-competent virus from a cohort of 10 ES. We successfully cultured six replication-competent isolates from 4 of the 10 ES. The frequency of latently infected cells in these patients was more than a log lower than that seen in patients on highly active antiretroviral therapy with undetectable viral loads. Full-length sequencing of all six isolates revealed no large deletions in any of the genes. A few mutations and small insertions and deletions were found in some isolates, but phenotypic analysis of the affected genes suggested that their function remained intact. Furthermore, all six isolates replicated as well as standard laboratory strains in vitro. The results suggest that some ES are infected with HIV-1 isolates that are fully replication competent and that long-term immunologic control of replication-competent HIV-1 is possible.
MUC1 Induced by Epstein-Barr Virus Latent Membrane Protein 1 Causes Dissociation of the Cell-Matrix Interaction and Cellular Invasiveness via STAT Signaling
Authors: Kondo Satoru , Yoshizaki Tomokazu , Wakisaka Naohiro , Horikawa Toshiyuki , Murono Shigeyuki , Jang Kyung Lib , Joab Irene , Furukawa Mitsuru , Pagano Joseph S. 
Published: December 2006

ABSTRACT
Disruption of cellular adhesion is an essential pathobiologic step leading to tumor dissemination. Mucin 1 (MUC1) is a mucinous glycoprotein expressed at the surfaces of epithelial cells in many tissues and their carcinomas. MUC1 plays crucial roles in tumor invasion and metastasis, especially in opposing cell adhesion. We have shown that virus infection, specifically by the human tumor virus Epstein-Barr virus (EBV) induces a spectrum of cellular invasiveness and metastasis factors. Here we show that expression of MUC1 is increased in diverse latently EBV-infected cell lines that express latent membrane protein 1 (LMP1), the main viral oncoprotein, and that the level of MUC1 was suppressed by expression of a dominant-negative mutant of LMP1. Expression of LMP1 in EBV-negative nasopharyngeal cell lines induces expression of MUC1 through activation of the MUC1 promoter via binding of STAT1 and STAT3. Finally, LMP1 reduces cell adhesion ability, which is restored by inhibition of MUC1 expression with MUC1 small interfering RNA (siRNA). In addition, LMP1 increases cell invasiveness, which is suppressed by MUC1 siRNA. Thus, LMP1 induces MUC1, a factor important in an early step of detachment and release of tumor cells, which along with induction of other invasiveness and angiogenic factors may combine to act in a complex sequential process that culminates in metastasis of EBV-infected tumor cells.
Mapping of Key Functions of the Herpes Simplex Virus 1 U
S
3 Protein Kinase: the U
S
3 Protein Can Form Functional Heteromultimeric Structures Derived from Overlapping Truncated Polypeptides
Authors: Poon Alice P. W. , Roizman Bernard 
Published: December 2006

ABSTRACT

Earlier studies have shown that the herpes simplex virus (HSV) U
S
3 encodes two transcriptional units directing the synthesis of the U
S
3 (residues 1 to 481) and U
S
3.5 (residues 77 to 481) protein kinases. Both kinases phosphorylate histone deacetylase 1 (HDAC1) and HDAC2 and enable the expression of genes cotransduced into U2OS cells by recombinant baculoviruses, an activity designated the “helper function.” The two kinases differ with respect to antiapoptotic activity. In the studies reported here, we made a series of FLAG-tagged amino- and carboxyl-terminal truncations of U
S
3 and these were tested for antiapoptotic activity, phosphorylation of HDAC1, and the helper function. We report the following. (i) HDAC1 phosphorylation and the helper function were expressed in cells transduced by the truncation encoding residues 182 to 481 but not in cells transduced by the truncation encoding residues 189 to 481 or the amino-terminal polypeptides encompassing the first 188 amino acids. (ii) The self-posttranslational modification requires residues 164 to 481. (iii) The antiapoptotic activity requires both the amino-terminal and the carboxyl-terminal domains, of which the truncated protein containing residues 1 to 163 and that containing residues 164 to 481, respectively, were the smallest fragments tested to be effective. The two domains need not be on the same molecule, but they must overlap. The smallest overlapping pair tested was the fragment containing residues 1 to 181 and that containing residues 164 to 481. Consistent with the hypothesis that the effective overlapping truncations form a heteromultimeric structure, antibody to FLAG coprecipitated untagged U
S
3 from lysates of cells cotransduced with FLAG-tagged, truncated U
S
3 constructs. Although U
S
3 has been reported to be a monomeric enzyme, the results indicate that it can form enzymatically active multimeric structures.
A Kinetic Study of the Cytochrome c-Hydrogen Peroxide Reaction
Authors: Perez-Benito Joaquin F. 
Published: December 2006

The kinetics of the reaction of cytochromecwith H2O2was studied in aqueous phosphate media near physiological pH (5.7-7.2). The UV-VIS spectra indicated that the heme prosthetic group of the protein suffered an oxidative degradation during the reaction. The experimental rate law wasv=kexp[cytochromec] [H2O2], withkexp= (A+B[H+])/(1 +C[H+]). The apparent activation parameters associated withkexpwereEa= 46 ± 2 kJ mol-1, ∆Ho≠= 43 ± 2 kJ mol-1and ∆So≠= -111 ± 5 J K-1mol-1. The reaction showed base catalysis and was also catalyzed by both CrO42-and acrylamide. It was inhibited by the oxidants WO42-, MoO42-, VO3-and [Fe(CN)6]3-as well as by the reductants [Fe(CN)6]4-and D-mannitol, whereas Zn2+and superoxide dismutase had no appreciable effect. The results are consistent with initial reduction of iron from Fe(III) to Fe(II) (supported by inhibition caused by most oxidants), followed by a hydroxyl-radical mediated oxidative degradation of the heme prosthetic group (supported by the inhibition caused by both [Fe(CN)6]4-and D-mannitol).