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  • 1
    Article
    Article
    Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein
    2015
    ISSN: 0036-8075 
    Details
    Language: English
    In: Science (American Association for the Advancement of Science), 2015-07-17, Vol.349 (6245), p.309-312
    Description: Morphinan alkaloids from the opium poppy are used for pain relief. The direction of metabolites to morphinan biosynthesis requires isomerization of (S)- to (R)-reticuline. Characterization of high-reticuline poppy mutants revealed a genetic locus, designated STORR [(S)- to (R)-reticuline] that encodes both cytochrome P450 and oxidoreductase modules, the latter belonging to the aldo-keto reductase family. Metabolite analysis of mutant alleles and heterologous expression demonstrate that the P450 module is responsible for the conversion of (S)-reticuline to 1,2-dehydroreticuline, whereas the oxidoreductase module converts 1,2-dehydroreticuline to (R)-reticuline rather than functioning as a P450 redox partner. Proteomic analysis confirmed that these two modules are contained on a single polypeptide in vivo. This modular assembly implies a selection pressure favoring substrate channeling. The fusion protein STORR may enable microbial-based morphinan production.
    Subject(s): Biosynthesis ; Enzymes ; Metabolites ; Modules ; Morphine ; Narcotics ; Pathways ; Poppies ; Proteins ; REPORTS
    ISSN: 0036-8075
    E-ISSN: 1095-9203
    DOI: 10.1126/science.aab1852
    Source: JSTOR Life Sciences
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
    Source: Get It Now
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  • 2
    Article
    Article
    FOXP3 Expression Is Upregulated in CD4+T Cells in Progressive HIV-1 Infection and Is a Marker of Disease Severity
    2010
    ISSN: 1932-6203 
    Details
    Language: English
    In: PloS one, 2010-07-23, Vol.5 (7), p.e11762
    Description: Understanding the role of different classes of T cells during HIV infection is critical to determining which responses correlate with protective immunity. To date, it is unclear whether alterations in regulatory T cell (Treg) function are contributory to progression of HIV infection. FOXP3 expression was measured by both qRT-PCR and by flow cytometry in HIV-infected individuals and uninfected controls together with expression of CD25, GITR and CTLA-4. Cultured peripheral blood mononuclear cells were stimulated with anti-CD3 and cell proliferation was assessed by CFSE dilution. HIV infected individuals had significantly higher frequencies of CD4+FOXP3+ T cells (median of 8.11%; range 1.33%-26.27%) than healthy controls (median 3.72%; range 1.3-7.5%; P=0.002), despite having lower absolute counts of CD4+FOXP3+ T cells. There was a significant positive correlation between the frequency of CD4+FOXP3+ T cells and viral load (rho=0.593 P=0.003) and a significant negative correlation with CD4 count (rho=-0.423 P=0.044). 48% of our patients had CD4 counts below 200 cells/kl and these patients showed a marked elevation of FOXP3 percentage (median 10% range 4.07%-26.27%). Assessing the mechanism of increased FOXP3 frequency, we found that the high FOXP3 levels noted in HIV infected individuals dropped rapidly in unstimulated culture conditions but could be restimulated by T cell receptor stimulation. This suggests that the high FOXP3 expression in HIV infected patients is likely due to FOXP3 upregulation by individual CD4+ T cells following antigenic or other stimulation. FOXP3 expression in the CD4+ T cell population is a marker of severity of HIV infection and a potential prognostic marker of disease progression.
    Subject(s): Acquired immune deficiency syndrome ; AIDS ; Antigens ; CD25 antigen ; CD3 antigen ; CD4 antigen ; Cell culture ; Cell proliferation ; Cellular Microbiology and Pathogenesis ; Correlation ; CTLA-4 protein ; Cytokines ; Cytometry ; Dilution ; Flow cytometry ; Foxp3 protein ; Growth factors ; Hematology ; HIV ; HIV Infection and AIDS ; Human immunodeficiency virus ; Human immunodeficiency virus 1 ; Immune Response ; Immunity ; Immunity to Infections ; Immunology ; Immunomodulation ; Infections ; Infectious Diseases ; Laboratories ; Leukocytes (mononuclear) ; Lymphocytes ; Lymphocytes T ; Medicine ; Patients ; Peripheral blood mononuclear cells ; Stimulation ; T cell receptors ; T-cell receptor ; Transcription factors ; Tuberculosis ; Viral infections
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    DOI: 10.1371/journal.pone.0011762
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 3
    Article
    Article
    Host CCL3L1 Gene Copy Number in Relation to HIV-1-Specific CD4+ and CD8+ T-Cell Responses and Viral Load in South African Women
    2008
    ISSN: 1525-4135 
    Details
    Language: English
    In: Journal of acquired immune deficiency syndromes (1999), 2008, Vol.48 (3), p.245-254
    Description: HIV-specific T-cell responses play an important role in control of infection. Because CCL3 has immune modulatory and antiviral activities, we hypothesized that host CCL3 genotype (CCL3L1 gene duplications) would influence the development of effective HIV-specific immune responses. Copy numbers of CCL3L1 were determined for 71 HIV-infected women, and HIV-specific CD4 and CD8 T-cell responses to overlapping peptide pools spanning the HIV-1 subtype C genome were simultaneously measured by an interferon-gamma and interleukin-2 whole-blood flow cytometric assay. Host CCL3L1 copy number correlated negatively with viral load (r=-0.239, P=0.045), as did magnitudes of Gag CD4 (r=-0.362, P=0.002) and CD8 (r=-0.261, P=0.028) T-cell responses. Patients with a Gag CD4 response (P=0.002) or dominant Gag CD8 (P=0.006) response had significantly lower viral loads than those whose dominant response targeted another region of the genome, whereas a dominant Nef-specific CD8 T-cell response was associated with higher HIV viral load. CCL3L1 copy number greater than or equal to the population median of 5 was significantly associated with increased magnitude of CD4 Gag responses (P=0.017), and women who had CD4 and CD8 Gag-specific responses had significantly lower viral loads (P=0.004) and higher CCL3L1 copy number (P=0.015) than those women with only CD8 Gag-specific responses.
    Subject(s): Adolescent ; Adult ; Biological and medical sciences ; CCL3L1 copy number ; CD4+ and CD8+ T cell responses ; CD4-Positive T-Lymphocytes - immunology ; CD8-Positive T-Lymphocytes - immunology ; Chemokine CCL3 - genetics ; Cytokines ; Disease Progression ; Female ; Fundamental and applied biological sciences. Psychology ; Gene Dosage ; Gene Duplication ; Genes ; Genotype & phenotype ; HIV ; HIV Infections - genetics ; HIV Infections - immunology ; HIV-1 - immunology ; HIV-1 subtype C ; Human immunodeficiency virus ; Human immunodeficiency virus 1 ; Human viral diseases ; Humans ; Infectious diseases ; Lymphocyte Count ; Medical sciences ; Microbiology ; Miscellaneous ; South Africa ; T cell receptors ; Viral diseases ; Viral Load ; Virology ; Womens health
    ISSN: 1525-4135
    E-ISSN: 1944-7884
    DOI: 10.1097/QAI.0b013e31816fdc77
    Source: Freely Accessible Journals
    Source: Journals@Ovid LWW Total Access Archive Collection 2021 Coverage to 2016 (LTOT-16-A21)
    URL: http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20488413$$DView record in Pascal Francis
    URL: https://www.ncbi.nlm.nih.gov/pubmed/18360285$$D View this record in MEDLINE/PubMed
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  • 4
    Article
    Article
    Reduced ability of newborns to produce CCL3 is associated with increased susceptibility to perinatal human immunodeficiency virus 1 transmission
    2006
    ISSN: 0022-1317 
    Details
    Language: English
    In: Journal of general virology, 2006-07-01, Vol.87 (7), p.2055-2065
    Description: 1 AIDS Virus Research Unit, National Institute for Communicable Diseases, and Department of Virology, University of the Witwatersrand, Private Bag X4, Sandringham, Johannesburg 2131, South Africa 2 Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, Soweto, South Africa 3 Gertrude H. Sergievsky Centre, College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA Correspondence Caroline T. Tiemessen carolinet{at}nicd.ac.za The role of CC chemokines in protection against mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission is not well understood. It was observed that mitogen-induced production of CCL3 and CCL4 by cord-blood mononuclear cells was increased among infants born to HIV-positive compared with HIV-negative mothers, and that a deficiency in production of CCL3 was associated with increased susceptibility to intrapartum HIV-1 infection. CCL3-L1 gene copy number was associated with CCL3 production and with vertical transmission. However, at equivalent CCL3-L1 gene copy numbers, infants who acquired HIV-1 infection relative to their exposed but uninfected counterparts had lower production of CCL3, suggesting that they may harbour some non-functional copies of this gene. Nucleotide changes that may influence CCL3 production were evident in the CCL3 and CCL3-L1 genes upstream of exon 2. Our findings suggest that infants who display a deficient-production phenotype of CCL3 are at increased risk of acquiring HIV-1, indicating that this chemokine in particular plays an essential role in protective immunity.
    Subject(s): Base Sequence ; Biological and medical sciences ; Chemokine CCL3 ; Chemokine CCL4 ; Chemokine CCL5 ; Chemokines, CC - biosynthesis ; Chemokines, CC - blood ; Chemokines, CC - genetics ; Cohort Studies ; DNA - genetics ; Female ; Fetal Blood - immunology ; Fundamental and applied biological sciences. Psychology ; Gene Dosage ; HIV Infections - immunology ; HIV Infections - transmission ; HIV Seronegativity - immunology ; HIV-1 ; Human immunodeficiency virus 1 ; Humans ; In Vitro Techniques ; Infant ; Infant, Newborn ; Infectious Disease Transmission, Vertical ; Leukocytes, Mononuclear - drug effects ; Leukocytes, Mononuclear - immunology ; Macrophage Inflammatory Proteins - biosynthesis ; Macrophage Inflammatory Proteins - blood ; Microbiology ; Miscellaneous ; Mitogens - pharmacology ; Polymorphism, Single Nucleotide ; Pregnancy ; Virology
    ISSN: 0022-1317
    E-ISSN: 1465-2099
    DOI: 10.1099/vir.0.81709-0
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: Alma/SFX Local Collection
    URL: http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17904402$$DView record in Pascal Francis
    URL: https://www.ncbi.nlm.nih.gov/pubmed/16760409$$D View this record in MEDLINE/PubMed
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  • 5
    Article
    Article
    FOXP3 expression is upregulated in CD4T cells in progressive HIV-1 infection and is a marker of disease severity
    2010
    Details
    Language: English
    In: PloS one, 2010-07-23, Vol.5 (7), p.e11762-e11762
    Description: Understanding the role of different classes of T cells during HIV infection is critical to determining which responses correlate with protective immunity. To date, it is unclear whether alterations in regulatory T cell (Treg) function are contributory to progression of HIV infection. FOXP3 expression was measured by both qRT-PCR and by flow cytometry in HIV-infected individuals and uninfected controls together with expression of CD25, GITR and CTLA-4. Cultured peripheral blood mononuclear cells were stimulated with anti-CD3 and cell proliferation was assessed by CFSE dilution. HIV infected individuals had significantly higher frequencies of CD4(+)FOXP3(+) T cells (median of 8.11%; range 1.33%-26.27%) than healthy controls (median 3.72%; range 1.3-7.5%; P = 0.002), despite having lower absolute counts of CD4(+)FOXP3(+) T cells. There was a significant positive correlation between the frequency of CD4(+)FOXP3(+) T cells and viral load (rho = 0.593 P = 0.003) and a significant negative correlation with CD4 count (rho = -0.423 P = 0.044). 48% of our patients had CD4 counts below 200 cells/microl and these patients showed a marked elevation of FOXP3 percentage (median 10% range 4.07%-26.27%). Assessing the mechanism of increased FOXP3 frequency, we found that the high FOXP3 levels noted in HIV infected individuals dropped rapidly in unstimulated culture conditions but could be restimulated by T cell receptor stimulation. This suggests that the high FOXP3 expression in HIV infected patients is likely due to FOXP3 upregulation by individual CD4(+) T cells following antigenic or other stimulation. FOXP3 expression in the CD4(+) T cell population is a marker of severity of HIV infection and a potential prognostic marker of disease progression.
    Subject(s): Antibodies - immunology ; Antibodies - pharmacology ; Antigens, CD - genetics ; Case-Control Studies ; CD3 Complex - immunology ; CD4-Positive T-Lymphocytes - metabolism ; Cell Proliferation - drug effects ; CTLA-4 Antigen ; Flow Cytometry ; Forkhead Transcription Factors - genetics ; Glucocorticoid-Induced TNFR-Related Protein ; HIV Infections - genetics ; HIV Infections - physiopathology ; Interleukin-2 Receptor alpha Subunit - genetics ; Leukocytes, Mononuclear - cytology ; Leukocytes, Mononuclear - drug effects ; Receptors, Nerve Growth Factor - genetics ; Receptors, Tumor Necrosis Factor - genetics ; Reverse Transcriptase Polymerase Chain Reaction
    E-ISSN: 1932-6203
    DOI: 10.1371/journal.pone.0011762
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    URL: https://www.ncbi.nlm.nih.gov/pubmed/20668701$$D View this record in MEDLINE/PubMed
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  • 6
    Article
    Article
    FOXP3 Expression Is Upregulated in CD4.sup.+T Cells in Progressive HIV-1 Infection and Is a Marker of Disease Severity
    2010
    ISSN: 1932-6203 
    Details
    Language: English
    In: PloS one, 2010-07-23, Vol.5 (7), p.e11762
    Description: Background Understanding the role of different classes of T cells during HIV infection is critical to determining which responses correlate with protective immunity. To date, it is unclear whether alterations in regulatory T cell (Treg) function are contributory to progression of HIV infection. Methodology FOXP3 expression was measured by both qRT-PCR and by flow cytometry in HIV-infected individuals and uninfected controls together with expression of CD25, GITR and CTLA-4. Cultured peripheral blood mononuclear cells were stimulated with anti-CD3 and cell proliferation was assessed by CFSE dilution. Principal Findings HIV infected individuals had significantly higher frequencies of CD4.sup.+ FOXP3.sup.+ T cells (median of 8.11%; range 1.33%-26.27%) than healthy controls (median 3.72%; range 1.3-7.5%; P = 0.002), despite having lower absolute counts of CD4.sup.+ FOXP3.sup.+ T cells. There was a significant positive correlation between the frequency of CD4.sup.+ FOXP3.sup.+ T cells and viral load (rho = 0.593 P = 0.003) and a significant negative correlation with CD4 count (rho = -0.423 P = 0.044). 48% of our patients had CD4 counts below 200 cells/[micro]l and these patients showed a marked elevation of FOXP3 percentage (median 10% range 4.07%-26.27%). Assessing the mechanism of increased FOXP3 frequency, we found that the high FOXP3 levels noted in HIV infected individuals dropped rapidly in unstimulated culture conditions but could be restimulated by T cell receptor stimulation. This suggests that the high FOXP3 expression in HIV infected patients is likely due to FOXP3 upregulation by individual CD4.sup.+ T cells following antigenic or other stimulation. Conclusions/Significance FOXP3 expression in the CD4.sup.+ T cell population is a marker of severity of HIV infection and a potential prognostic marker of disease progression.
    Subject(s): Development and progression ; Health aspects ; HIV (Viruses) ; HIV infection ; HIV patients ; T cells
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    DOI: 10.1371/journal.pone.0011762
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 7
    Article
    Article
    Plant science. Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein
    2015
    Details
    Language: English
    In: Science (American Association for the Advancement of Science), 2015-07-17, Vol.349 (6245), p.309-312
    Description: Morphinan alkaloids from the opium poppy are used for pain relief. The direction of metabolites to morphinan biosynthesis requires isomerization of (S)- to (R)-reticuline. Characterization of high-reticuline poppy mutants revealed a genetic locus, designated STORR [(S)- to (R)-reticuline] that encodes both cytochrome P450 and oxidoreductase modules, the latter belonging to the aldo-keto reductase family. Metabolite analysis of mutant alleles and heterologous expression demonstrate that the P450 module is responsible for the conversion of (S)-reticuline to 1,2-dehydroreticuline, whereas the oxidoreductase module converts 1,2-dehydroreticuline to (R)-reticuline rather than functioning as a P450 redox partner. Proteomic analysis confirmed that these two modules are contained on a single polypeptide in vivo. This modular assembly implies a selection pressure favoring substrate channeling. The fusion protein STORR may enable microbial-based morphinan production.
    Subject(s): Base Sequence ; Benzylisoquinolines - chemistry ; Benzylisoquinolines - metabolism ; Cytochrome P-450 Enzyme System - genetics ; Cytochrome P-450 Enzyme System - metabolism ; Genetic Loci ; Isoquinolines - chemistry ; Isoquinolines - metabolism ; Molecular Sequence Data ; Morphinans - chemistry ; Morphinans - metabolism ; Mutation ; Oxidation-Reduction ; Papaver - enzymology ; Papaver - genetics ; Plant Proteins - genetics ; Plant Proteins - metabolism ; Quaternary Ammonium Compounds - chemistry ; Quaternary Ammonium Compounds - metabolism
    E-ISSN: 1095-9203
    DOI: 10.1126/science.aab1852
    Source: JSTOR Life Sciences
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
    Source: Get It Now
    URL: https://www.ncbi.nlm.nih.gov/pubmed/26113639$$D View this record in MEDLINE/PubMed
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  • 8
    Article
    Article
    African infants' CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine
    2007
    ISSN: 0269-9370 
    Details
    Language: English
    In: AIDS (London), 2007, Vol.21 (13), p.1753-1761
    Description: Individuals with more copies of CCL3L1 (CCR5 ligand) than their population median have been found to be less susceptible to HIV infection. We investigated whether maternal or infant CCL3L1 gene copy numbers are associated with perinatal HIV transmission when single-dose nevirapine is given for prevention. A nested case-control study was undertaken combining data from four cohorts including 849 HIV-infected mothers and their infants followed prospectively in Johannesburg, South Africa. Access to antiretroviral drugs for the prevention of perinatal transmission differed across the cohorts. Maternal and infant CCL3L1 gene copy numbers per diploid genome (pdg) were determined by real-time polymerase chain reaction for 79 out of 83 transmitting pairs ( approximately 10% transmission rate) and 235 randomly selected non-transmitting pairs. Higher numbers of infant, but not maternal, CCL3L1 gene copies were associated with reduced HIV transmission (P = 0.004) overall, but the association was attenuated if mothers took single-dose nevirapine or if the maternal viral load was low. Maternal nevirapine was also associated with reduced spontaneously released CCL3 (P = 0.007) and phytohemagglutinin-stimulated CCL3 (P = 0.005) production in cord blood mononuclear cells from uninfected infants. We observed a strong association between higher infant CCL3L1 gene copies and reduced susceptibility to HIV in the absence of maternal nevirapine. We also observed a reduction in newborn CCL3 production with nevirapine exposure. Taken together, we hypothesize that nevirapine may have direct or indirect effects that partly modify the role of the CCR5 ligand CCL3 in HIV transmission, obscuring the relationship between this genetic marker and perinatal HIV transmission.
    Subject(s): Adult ; AIDS/HIV ; Anti-HIV Agents - therapeutic use ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Biological and medical sciences ; Case-Control Studies ; CCL3 ; Chemokine CCL3 ; Chemokine CCL4 ; Chemokine CCL5 ; chemokines ; Chemokines, CC - biosynthesis ; Chemokines, CC - genetics ; Female ; Fetal Blood - metabolism ; Genetic Predisposition to Disease ; HIV Infections - genetics ; HIV Infections - prevention & control ; HIV Infections - transmission ; HIV Infections - virology ; Human immunodeficiency virus ; Human viral diseases ; Humans ; Immunodeficiencies ; Immunodeficiencies. Immunoglobulinopathies ; Immunopathology ; Infant, Newborn ; Infectious Disease Transmission, Vertical ; Infectious diseases ; Male ; Medical sciences ; MIP1alpha ; mother-to-child HIV transmission ; nevirapine ; Nevirapine - therapeutic use ; Pharmacology. Drug treatments ; Pregnancy ; Pregnancy Complications, Infectious - virology ; Reverse Transcriptase Inhibitors - therapeutic use ; Viral diseases ; Viral diseases of the lymphoid tissue and the blood. Aids ; Viral Load
    ISSN: 0269-9370
    E-ISSN: 1473-5571
    DOI: 10.1097/QAD.0b013e3282ba553a
    Source: Hellenic Academic Libraries Link
    Source: Alma/SFX Local Collection
    URL: http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19043672$$DView record in Pascal Francis
    URL: https://www.ncbi.nlm.nih.gov/pubmed/17690574$$D View this record in MEDLINE/PubMed
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