bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alteration of the Leptin Network in Late Morbid Obesity Induced in Mice by Brain Infection with Canine Distemper Virus
Authors: Bernard Arlette , Cohen Richard , Khuth Seng-Thuon , Vedrine Bruno , Verlaeten Olivier , Akaoka Hideo , Giraudon Pascale , Belin Marie-Françoise 
Published: December 2019

ABSTRACT
Viruses can induce progressive neurologic disorders associated with diverse pathological manifestations, and therefore, viral infection of the brain can impair differentiated neural functions, depending on the initial viral tropism. We have previously reported that canine distemper virus (CDV) targets certain mouse brain structures, including the hypothalamus, early and selectively. Infected mice exhibit acute encephalitis, with late disease, characterized by motor impairment or obesity syndrome, appearing in some of the surviving mice several months after the initial viral replication. In the present study, we show viral persistence in the hypothalami of obese mice, as demonstrated by low, but still significant, levels of CDV nucleoprotein transcripts, associated with a dramatic decrease in F gene mRNAs. Given the pivotal role of the hypothalamus in obesity (eating behavior, energy consumption, and neuroendocrine function) and that of leptin, the adipose tissue-derived satiety factor acting through hypothalamic receptors, we analyzed the leptin networks in both obese and nonobese mice. The discrepancy found between the chronic and dramatic increase in blood leptin levels and the occurrence of obesity may be due to leptin resistance in the brain. In fact, expression of the long leptin receptor isoform, representing the functional leptin receptor, was specifically downregulated in the hypothalami of obese mice, explaining their inability to generate an adequate response to leptin in the brain. Intriguingly, during the acute phase of infection, its expression was increased in CDV-targeted structures in all infected mice and remained high in obese mice in all CDV-targeted structures, except for the hypothalamus. The biphasic change in hypothalamic leptin receptor expression seen during the progression of CDV-induced obesity provides a new paradigm for understanding mechanisms of neuroendocrinological, virus-induced abnormalities.
Functional Analysis of Human Herpesvirus 8-Encoded Viral Interferon Regulatory Factor 1 and Its Association with Cellular Interferon Regulatory Factors and p300
Authors: Burýšek Ladislav , Yeow Wen-Shuz , Lubyová Barbora , Kellum Merrill , Schafer Susan L. , Huang Yao Qi , Pitha Paula M. 
Published: December 2019

ABSTRACTHuman herpesvirus 8/Kaposi sarcoma-associated virus (HHV-8/KSHV) contains, in addition to genes required for viral replication, a unique set of nonstructural genes which may be part of viral mimicry and contribute to viral replication and pathogenesis in vivo. Among these, HHV-8 encodes four open reading frames (ORFs) that showed homology to the transcription factors of the interferon regulatory factor (IRF) family. The ORF K9, viral IRF 1 (vIRF-1), has been cloned, and it was shown that, when overexpressed, it down modulates the interferon-mediated transcriptional activation of the interferon-stimulated gene 15 (ISG 15) promoter, and the role of vIRF-1 in viral mimicry was implied. However, the molecular mechanism of this effect has not been clarified. Here, we extend this observation and show that vIRF-1 also downregulates the transcriptional activity of IFNA gene promoter in infected cells by interfering with the transactivating activity of cellular IRFs, including IRF-1 and IRF-3. We further show that ectopic expression of vIRF-1 in NIH 3T3 cells confers resistance to tumor necrosis factor alpha-induced apoptosis. While vIRF-1 is unable to bind DNA with the same specificity as cellular IRFs, we demonstrate by in vitro binding assay that it can associate with the family of cellular IRFs, such as IRF-1 and the interferon consensus sequence binding protein. vIRF-1 interaction domain was localized between amino acids (aa) 152 and 243. While no binding between the full-size IRF-3 and vIRF-1 could be detected by the same assay, we show that vIRF-1 also targets the carboxy-terminal region (aa 1623 to 2414) of the transcriptional coactivator p300 which could also bind IRF-3 and IRF-1. These results demonstrate that vIRF-1 can modulate the transcription of the IFNA genes by direct heterodimerization with members of the IRF family, as well as by competitive binding with cellular transcription factors to the carboxy-terminal region of p300.
Reassortment and Insertion-Deletion Are Strategies for the Evolution of Influenza B Viruses in Nature
Authors: McCullers Jonathan A. , Wang George C. , He Shiqin , Webster Robert G. 
Published: December 2019

ABSTRACT
The evolution of influenza B viruses is poorly understood. Reassortment of influenza B viruses in nature as a means of genetic variation has not been considered to be a major contributor to their evolution. However, the current practice of assigning evolutionary relationships by antigenic analysis of the hemagglutinin of influenza B viruses would fail to detect reassortants. In this study, influenza B viruses isolated within the past 10 years from sites in the United States and China were studied by nucleotide sequencing of the hemagglutinin and neuraminidase genes and construction of phylogenetic trees to assess evolutionary relationships. A group of viruses represented by B/Houston/1/92 possess a hemagglutinin derived from a B/Yamagata/16/88-like strain and a neuraminidase derived from a B/Victoria/2/87-like strain. A second reassortment event between the hemagglutinin of a B/Yamagata/16/88-like virus closely related to the B/Beijing/184/93 strain and the neuraminidase of a B/Victoria/2/87-like strain is represented by a single virus, B/Memphis/3/93. The neuraminidase of the reassortant viruses is most closely related to that of B/Victoria/2/87-like viruses currently circulating in Nanchang, China. A pattern of insertions and deletions in the hemagglutinin and the neuraminidase of different strains of influenza B viruses is observed. Reassortment plays a role in the evolution of influenza B viruses and may necessitate a change in the methods used to assess and identify new influenza viruses.
Characterization of a Highly Replicative Intergroup M/O Human Immunodeficiency Virus Type 1 Recombinant Isolated from a Cameroonian Patient
Authors: Peeters Martine , Liegeois Florian , Torimiro Ndongo , Bourgeois Anke , Mpoudi Eitel , Vergne Laurence , Saman Eric , Delaporte Eric , Saragosti Sentob 
Published: December 2019

ABSTRACT

A Cameroonian patient with antibodies reacting simultaneously to human immunodeficiency virus type 1 (HIV-1) group O- and group M-specific V3-loop peptides was identified. In order to confirm that this patient was coinfected with both viruses, PCRs with O- and M-specific discriminating primers corresponding to different regions of the genome were carried out with both primary lymphocyte DNA and the corresponding viral strains isolated from three consecutive patient samples. The PCR data suggested that this patient is coinfected with a group M virus and a recombinant M/O virus. Indeed, only type M
gag
sequences could be amplified, while for the
env
region, both type M and O sequences were amplified, from plasma or from DNA extracted from primary lymphocytes. Sequence analysis of a complete recombinant genome isolated from the second sample (97CA-MP645 virus isolate) revealed two intergroup breakpoints, one in the
vpr
gene and the second in the long terminal repeat region around the TATA box. Comparison of the type M sequences shared by the group M and the recombinant M/O viruses showed that these sequences were closely related, with only 3% genetic distance, suggesting that the M virus was one of the parental viruses. In this report we describe for the first time a recombination event in vivo between viruses belonging to two different groups, leading to a replicative virus. Recombination between strains with such distant lineages (65% overall homology) may contribute substantially to the emergence of new HIV-1 variants. We documented that this virus replicates well and became predominant in vitro. At this time, group O viruses represent a minority of the strains responsible for the HIV-1 pandemic. If such recombinant intergroup viruses gained better fitness, inducing changes in their biological properties compared to the parental group O virus, the prevalences of group O sequences could increase rapidly. This will have important implications for diagnosis of HIV-1 infections by serological and molecular tests, as well as for antiviral treatment.
Roles for the E4 orf6, orf3, and E1B 55-Kilodalton Proteins in Cell Cycle-Independent Adenovirus Replication
Authors: Goodrum Felicia D. , Ornelles David A. 
Published: December 2019

ABSTRACT

Adenoviruses bearing lesions in the E1B 55-kDa protein (E1B 55-kDa) gene are restricted by the cell cycle such that mutant virus growth is most impaired in cells infected during G
1
and least restricted in cells infected during S phase (F. D. Goodrum and D. A. Ornelles, J. Virol. 71:548–561, 1997). A similar defect is reported here for E4 orf6-mutant viruses. An E4 orf3-mutant virus was not restricted for growth by the cell cycle. However, orf3 was required for enhanced growth of an E4 orf6-mutant virus in cells infected during S phase. The cell cycle restriction may be linked to virus-mediated mRNA transport because both E1B 55-kDa- and E4 orf6-mutant viruses are defective at regulating mRNA transport at late times of infection. Accordingly, the cytoplasmic-to-nuclear ratio of late viral mRNA was reduced in G
1
cells infected with the mutant viruses compared to that in G
1
cells infected with the wild-type virus. By contrast, this ratio was equivalent among cells infected during S phase with the wild-type or mutant viruses. Furthermore, cells infected during S phase with the E1B 55-kDa- or E4 orf6-mutant viruses synthesized more late viral protein than did cells infected during G
1
. However, the total amount of cytoplasmic late viral mRNA was greater in cells infected during G
1
than in cells infected during S phase with either the wild-type or mutant viruses, indicating that enhanced transport of viral mRNA in cells infected during S phase cannot account for the difference in yields in cells infected during S phase and in cells infected during G
1
. Thus, additional factors affect the cell cycle restriction. These results indicate that the E4 orf6 and orf3 proteins, in addition to the E1B 55-kDa protein, may cooperate to promote cell cycle-independent adenovirus growth.
Inhibitory Mechanism of the CXCR4 Antagonist T22 against Human Immunodeficiency Virus Type 1 Infection
Authors: Murakami Tsutomu , Zhang Tian-Yuan , Koyanagi Yoshio , Tanaka Yuetsu , Kim Jin , Suzuki Yoichi , Minoguchi Shigeru , Tamamura Hirokazu , Waki Michinori , Matsumoto Akiyoshi , Fujii Nobutaka , Shida Hisatoshi , Hoxie James A. , Peiper Stephen C. , Yamamoto Naoki 
Published: December 2019

ABSTRACT

We recently reported that a cationic peptide, T22 ([Tyr
5,12
, Lys
7
]-polyphemusin II), specifically inhibits human immunodeficiency virus type 1 (HIV-1) infection mediated by CXCR4 (T. Murakami et al., J. Exp. Med. 186:1389–1393, 1997). Here we demonstrate that T22 effectively inhibits replication of T-tropic HIV-1, including primary isolates, but not of non-T-tropic strains. By using a panel of chimeric viruses between T- and M-tropic HIV-1 strains, viral determinants for T22 susceptibility were mapped to the V3 loop region of gp120. T22 bound to CXCR4 and interfered with stromal-cell-derived factor-1α–CXCR4 interactions in a competitive manner. Blocking of anti-CXCR4 monoclonal antibodies by T22 suggested that the peptide interacts with the N terminus and two of the extracellular loops of CXCR4. Furthermore, the inhibition of cell-cell fusion in cells expressing CXCR4/CXCR2 chimeric receptors suggested that determinants for sensitivity of CXCR4 to T22 include the three extracellular loops of the coreceptor.
Envelope-Dependent Restriction of Human Immunodeficiency Virus Type 1 Spreading in CD4+T Lymphocytes: R5 but Not X4 Viruses Replicate in the Absence of T-Cell Receptor Restimulation
Authors: Vicenzi Elisa , Bordignon Paola Panina , Biswas Priscilla , Brambilla Andrea , Bovolenta Chiara , Cota Manuela , Sinigaglia Francesco , Poli Guido 
Published: December 2019

ABSTRACTThe human immunodeficiency virus (HIV) replicates in activated CD4+T lymphocytes. However, only CD4+Th2 and Th0, but not Th1, CD4+T-cell clones have been reported to efficiently support HIV-1 replication. This dichotomous pattern was further investigated in the present study in Th1, Th2, or Th0 cell lines derived from umbilical human cord blood and in T-cell clones obtained from the peripheral blood mononuclear cells (PBMC) of healthy adults. Both primary and laboratory-adapted HIV-1 strains with CCR5 as the exclusive entry coreceptor (R5 viruses) efficiently replicated in Th1, Th2, and Th0 cells. In sharp contrast, CXCR4-dependent (X4) viruses poorly replicated in both polarized and unpolarized CD4+T cells, including adults’ PBMC infected several days after mitogenic stimulation. Unlike the X4 HIV-1NL4-3, a chimera in which theenvgene had been replaced with that of the R5 HIV-1NL(AD8), efficiently replicated in both Th1 and Th2 cells. This X4-dependent restriction of HIV replication was not explained by either the absence of functional CXCR4 on the cell surface or by the inefficient viral entry and reverse transcription. T-cell receptor stimulation by anti-CD3 monoclonal antibodies fully rescued X4 HIV-1 replication in both Th1 and Th2 cells, whereas it did not alter the extent and kinetics of R5 HIV-1 spreading. Thus, R5 HIVs show a replicative advantage in comparison to X4 viruses in their ability to efficiently propagate among suboptimally activated T lymphocytes, regardless of their polarized or unpolarized functional profiles. This observation may help to explain the absolute predominance of R5 HIVs over X4 viruses observed after viral transmission and during early-stage disease.
Effective Induction of Simian Immunodeficiency Virus-Specific Cytotoxic T Lymphocytes in Macaques by Using a Multiepitope Gene and DNA Prime-Modified Vaccinia Virus Ankara Boost Vaccination Regimen
Authors: Hanke Tomas , Samuel Rachel V. , Blanchard Tom J. , Neumann Veronica C. , Allen Todd M. , Boyson Jon E. , Sharpe Sally A. , Cook Nicola , Smith Geoffrey L. , Watkins David I. , Cranage Martin P. , McMichael Andrew J. 
Published: December 2019

ABSTRACTDNA and modified vaccinia virus Ankara (MVA) are vaccine vehicles suitable and safe for use in humans. Here, by using a multicytotoxic T-lymphocyte (CTL) epitope gene and a DNA prime-MVA boost vaccination regimen, high levels of CTLs specific for a single simian immunodeficiency virus (SIV)gag-derived epitope were elicited in rhesus macaques. These vaccine-induced CTLs were capable of killing SIV-infected cells in vitro. Fluorescence-activated cell sorter analysis using soluble tetrameric major histocompatibility complex-peptide complexes showed that the vaccinated animals had 1 to 5% circulating CD8+lymphocytes specific for the vaccine epitope, frequencies comparable to those in SIV-infected monkeys. Upon intrarectal challenge with pathogenic SIVmac251, no evidence for protection was observed in at least two of the three vaccinated animals. This study does not attempt to define correlates of protective immunity nor design a protective vaccine against immunodeficiency viruses, but it demonstrates clearly that the DNA prime-MVA boost regimen is an effective protocol for induction of CTLs in macaques. It also shows that powerful tools for studying the role of CTLs in the control of SIV and human immunodeficiency virus infections are now available: epitope-based vaccines, a protocol for an effective induction of CTLs in primates, and a simple and sensitive method for quantitation of epitope-specific T cells. The advantages of the DNA prime-MVA boost regimen as well as the correlations of tetramer staining of peripheral blood lymphocytes with CTL killing in vitro and postchallenge control of viremia are discussed.
Selection of Reversions and Suppressors of a Mutation in the CBF Binding Site of a Lymphomagenic Retrovirus
Authors: Martiney Marita J. , Rulli Karen , Beaty Robert , Levy Laura S. , Lenz Jack 
Published: December 2019

ABSTRACT
The retrovirus SL3 induces T-cell lymphomas in mice. The transcriptional enhancer in the long terminal repeat (LTR) of SL3 contains two 72-bp repeats. Each repeat contains a binding site for the transcription factor CBF (also called AML1). The CBF binding sites are called core elements. SAA is a mutant that is identical to SL3 except for the presence of a single-base-pair substitution in each of the two core elements. This mutation significantly attenuates viral lymphomagenicity. Most lymphomas that occur in SAA-infected mice contain proviruses with reversions or second-site suppressor mutations within the core element. We examined the selective pressures that might account for the predominance of the reversions and suppressor mutations in tumor proviruses by analyzing when proviruses with altered core sequences became abundant during the course of lymphomagenesis. Altered core sequences were easily detected in thymus DNAs by 4 to 6 weeks after SAA infection of mice, well before lymphomas were grossly evident. This result is consistent with the hypothesis that viruses with the core sequence alterations emerged because they replicated more effectively in mice than SAA. The number of 72-bp tandem, repeats in the viral LTR was found to vary, presumably as a consequence of reverse transcriptase slippage during polymerization. Proviruses with two repeats predominated in the thymuses of SAA- and SL3-infected mice before lymphomas developed, although LTRs with one or three repeats were also present. This suggested that two was the optimal number of 72-bp repeats for viral replication. However, in lymphomas, proviruses with three or four repeats usually predominated. This suggested that a late step in the process of lymphomagenesis led to the abundance of proviruses with additional repeats. We hypothesize that proviruses with additional 72-bp repeats endowed the cells containing them with a selective growth advantage.
Targeted Recombination Demonstrates that the Spike Gene of Transmissible Gastroenteritis Coronavirus Is a Determinant of Its Enteric Tropism and Virulence
Authors: Sánchez Carlos M. , Izeta Ander , Sánchez-Morgado Jose M. , Alonso Sara , Sola Isabel , Balasch Mónica , Plana-Durán Juan , Enjuanes Luis 
Published: December 2019

ABSTRACT

Targeted recombination within the S (spike) gene of transmissible gastroenteritis coronavirus (TGEV) was promoted by passage of helper respiratory virus isolates in cells transfected with a TGEV-derived defective minigenome carrying the S gene from an enteric isolate. The minigenome was efficiently replicated in
trans
and packaged by the helper virus, leading to the formation of true recombinant and pseudorecombinant viruses containing the S proteins of both enteric and respiratory TGEV strains in their envelopes. The recombinants acquired an enteric tropism, and their analysis showed that they were generated by homologous recombination that implied a double crossover in the S gene resulting in replacement of most of the respiratory, attenuated strain S gene (nucleotides 96 to 3700) by the S gene of the enteric, virulent isolate. The recombinant virus was virulent and rapidly evolved in swine testis cells by the introduction of point mutations and in-phase codon deletions in a domain of the S gene (nucleotides 217 to 665) previously implicated in the tropism of TGEV. The helper virus, with an original respiratory tropism, was also found in the enteric tract, probably because pseudorecombinant viruses carrying the spike proteins from the respiratory strain and the enteric virus in their envelopes were formed. These results demonstrated that a change in the tropism and virulence of TGEV can be engineered by sequence changes in the S gene.
The Cytotoxic T-Cell Response to Herpes Simplex Virus Type 1 Infection of C57BL/6 Mice Is Almost Entirely Directed against a Single Immunodominant Determinant
Authors: Wallace Morgan E. , Keating Rachael , Heath William R. , Carbone Francis R. 
Published: December 2019

ABSTRACTMany virus infections give rise to surprisingly limited T-cell responses directed to very few immunodominant determinants. We have been examining the cytotoxic T-lymphocyte (CTL) response to herpes simplex virus type 1 (HSV-1) infection. Previous studies have identified the glycoprotein B-derived peptide from residues 498 to 505 (gB498–505) as one of at least three determinants recognized by HSV-1-specific CTLs isolated from C57BL/6 mice. We had previously found that in vitro-derived CTLs directed to gB498–505show a characteristic pattern of T-cell receptor (TCR) usage, with 60% of gB498–505-specific CD8+T cells expressing BV10+TCR β chains and a further 20% expressing BV8S1. In this report, we confirm that this TCR V-region bias is also reflected in the ex vivo response to HSV-1 infection. A high proportion of activated CD8+draining lymph node cells were found to express these dominant V regions, suggesting that a substantial number of in vivo responding T cells were directed to this one viral determinant. The use of an HSV-1 deletion mutant lacking the gB498–505determinant in combination with accurate intracellular gamma interferon staining allowed us to quantify the extent of gB-specific T-cell dominance. Together, these results suggested that between 70 and 90% of all CD8+HSV-1-specific T cells target gB498–505. While deletion of this determinant resulted in an attenuated CD8+T-cell response, it also permitted the emergence of one or more previously unidentified cryptic specificities. Overall, HSV-1 infection of C57BL/6 mice results in an extremely focused pattern of CD8+T-cell selection in terms of target specificity and TCR expression.
Respiratory Mucosal Immunization with Reovirus Serotype 1/L Stimulates Virus-Specific Humoral and Cellular Immune Responses, Including Double-Positive (CD4+/CD8+) T Cells
Authors: Bhargava Periwal S. , Cebra John J. 
Published: December 2019

ABSTRACTRespiratory virus infections are a serious health challenge. A number of models that examine the nature of the respiratory immune response to particular pathogens exist. However, many pathogens that stimulate specific immunity in the lung are frequently not effective immunogens at other mucosal sites. A pathogen that is an effective respiratory as well as gastrointestinal immunogen would allow studies of the interaction between the mucosal sites. Reovirus (respiratory enteric orphan virus) serotype 1 is known to be an effective gut mucosal immunogen and provides a potential model for the relationship between the respiratory and the gut mucosal immune systems. In this study, we demonstrate that intratracheal immunization with reovirus 1/Lang (1/L) in C3H mice resulted in high titers of virus in the respiratory tract-associated lymphoid tissue (RALT). High levels of reovirus-specific immunoglobulin A were determined in the RALT fragment cultures. The major responding components of the bronchus-associated lymphoid tissue were the CD8+T lymphocytes. Cells from draining lymph nodes also exhibited lysis of reovirus-infected target cells after an in vitro culture. The present study also describes the distribution of transiently present CD4+/CD8+double-positive (DP) T cells in the mediastinal and tracheobronchial lymph nodes of RALT. CD4+/CD8+DP lymphocytes were able to proliferate in response to stimulation with viral antigen in culture. Furthermore, these cells exhibited lysis of reovirus-infected target cells after in vitro culture. These results establish reovirus 1/L as a viable model for future investigation of the mucosal immune response in the RALT and its relationship to the common mucosal immune system.