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  1. Article ; Online: A high dimensional immune monitoring model of HIV-specific CD8 T cell responses accurately identifies subjects achieving spontaneous control of viral replication

    Ndhlovu Zaza M / Chibnik Lori B / Proudfoot Jacqueline / Vine Seanna / McMullen Ashley / Cesa Kevin / Alvino Donna / Piechocka-Trocha Alicja / de Jager Philip L / Kaufmann Daniel E / Walker Bruce D

    Retrovirology, Vol 9, Iss Suppl 1, p P

    2012  Volume 19

    Keywords Medicine (General) ; R5-920 ; Medicine ; R ; DOAJ:Medicine (General) ; DOAJ:Health Sciences ; Immunologic diseases. Allergy ; RC581-607
    Language English
    Publishing date 2012-05-01T00:00:00Z
    Publisher BioMed Central
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Elite controllers with low to absent effector CD8+ T cell responses maintain highly functional, broadly directed central memory responses.

    Ndhlovu, Zaza M / Proudfoot, Jacqueline / Cesa, Kevin / Alvino, Donna Marie / McMullen, Ashley / Vine, Seanna / Stampouloglou, Eleni / Piechocka-Trocha, Alicja / Walker, Bruce D / Pereyra, Florencia

    Journal of virology

    2012  Volume 86, Issue 12, Page(s) 6959–6969

    Abstract: Analyses of the breadth and specificity of virus-specific CD8(+) T cell responses associated with control of HIV have largely relied on measurement of cytokine secretion by effector T cells. These have resulted in the identification of HIV elite ... ...

    Abstract Analyses of the breadth and specificity of virus-specific CD8(+) T cell responses associated with control of HIV have largely relied on measurement of cytokine secretion by effector T cells. These have resulted in the identification of HIV elite controllers with low or absent responses in which non-T-cell mechanisms of control have been suggested. However, successful control of HIV infection may be associated with central memory T cells, which have not been consistently examined in these individuals. Gag-specific T cells were characterized using a peptide-based cultured enzyme-linked immunosorbent spot assay (ELISpot). Peripheral blood mononuclear cells from HIV elite controllers (n = 10), progressors (n = 12), and antiretroviral-treated individuals (n = 9) were cultured with overlapping peptides for 12 days. Specificity was assessed by tetramer staining, functional features of expanded cells were assessed by cytokine secretion, and virus inhibition and phenotypic characteristics were assessed by cell sorting and coculture assays. After peptide stimulation, elite controllers showed a greater number of previously undetectable (new) responses compared to progressors (P = 0.0008). These responses were highly polyfunctional, with 64.5% of responses having 3 to 5 functions. Expandable epitope-specific CD8(+) T cells from elite controllers had strong virus inhibitory capacity and predominantly displayed a central memory phenotype. These data indicate that elite controllers with minimal T cell responses harbor a highly functional, broadly directed central memory T cell population that is capable of suppressing HIV in vitro. Comprehensive examination of this cell population could provide insight into the immune responses associated with successful containment of viremia.
    MeSH term(s) Adult ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/virology ; Female ; HIV Infections/immunology ; HIV Infections/virology ; HIV-1/immunology ; HIV-1/physiology ; Humans ; Immunologic Memory ; Male ; Middle Aged
    Language English
    Publishing date 2012-04-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.00531-12
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: High-dimensional immunomonitoring models of HIV-1-specific CD8 T-cell responses accurately identify subjects achieving spontaneous viral control.

    Ndhlovu, Zaza M / Chibnik, Lori B / Proudfoot, Jacqueline / Vine, Seanna / McMullen, Ashley / Cesa, Kevin / Porichis, Filippos / Jones, R Brad / Alvino, Donna Marie / Hart, Meghan G / Stampouloglou, Eleni / Piechocka-Trocha, Alicja / Kadie, Carl / Pereyra, Florencia / Heckerman, David / De Jager, Philip L / Walker, Bruce D / Kaufmann, Daniel E

    Blood

    2012  Volume 121, Issue 5, Page(s) 801–811

    Abstract: Unlabelled: The development of immunomonitoring models to determine HIV-1 vaccine efficacy is a major challenge. Studies suggest that HIV-1–specific CD8 T cells play a critical role in subjects achieving spontaneous viral control (HIV-1 controllers) and ...

    Abstract Unlabelled: The development of immunomonitoring models to determine HIV-1 vaccine efficacy is a major challenge. Studies suggest that HIV-1–specific CD8 T cells play a critical role in subjects achieving spontaneous viral control (HIV-1 controllers) and that they will be important in immune interventions. However, no single CD8 T-cell function is uniquely associated with controller status and the heterogeneity of responses targeting different epitopes further complicates the discovery of determinants of protective immunity. In the present study, we describe immunomonitoring models integrating multiple functions of epitope-specific CD8 T cells that distinguish controllers from subjects with treated or untreated progressive infection. Models integrating higher numbers of variables and trained with the least absolute shrinkage and selection operator (LASSO) variant of logistic regression and 10-fold cross-validation produce “diagnostic tests” that display an excellent capacity to delineate subject categories. The test accuracy reaches 75% area under the receiving operating characteristic curve in cohorts matched for prevalence of protective alleles. Linear mixed-effects model analyses show that the proliferative capacity, cytokine production, and kinetics of cytokine secretion are associated with HIV-1 control. Although proliferative capacity is the strongest single discriminant, integrated modeling of different dimensions of data leverages individual associations. This strategy may have important applications in predictive model development and immune monitoring of HIV-1 vaccine trials.
    Key points: Immune monitoring models integrating multiple functions of HIV-1-specific CD8 T cells distinguish controllers from subjects with progressive HIV-1 infection. This strategy may have important applications in predictive model development and immune monitoring of HIV-1 vaccine trials.
    MeSH term(s) AIDS Vaccines/immunology ; AIDS Vaccines/therapeutic use ; Adult ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/pathology ; Cytokines/immunology ; Female ; HIV Infections/immunology ; HIV Infections/pathology ; HIV Infections/therapy ; HIV-1/immunology ; Humans ; Immunologic Surveillance ; Kinetics ; Male ; Middle Aged ; Models, Immunological
    Chemical Substances AIDS Vaccines ; Cytokines
    Language English
    Publishing date 2012-12-11
    Publishing country United States
    Document type Clinical Trial ; Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood-2012-06-436295
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

    Pereyra, Florencia / Jia, Xiaoming / McLaren, Paul J / Telenti, Amalio / de Bakker, Paul I W / Walker, Bruce D / Ripke, Stephan / Brumme, Chanson J / Pulit, Sara L / Carrington, Mary / Kadie, Carl M / Carlson, Jonathan M / Heckerman, David / Graham, Robert R / Plenge, Robert M / Deeks, Steven G / Gianniny, Lauren / Crawford, Gabriel / Sullivan, Jordan /
    Gonzalez, Elena / Davies, Leela / Camargo, Amy / Moore, Jamie M / Beattie, Nicole / Gupta, Supriya / Crenshaw, Andrew / Burtt, Noël P / Guiducci, Candace / Gupta, Namrata / Gao, Xiaojiang / Qi, Ying / Yuki, Yuko / Piechocka-Trocha, Alicja / Cutrell, Emily / Rosenberg, Rachel / Moss, Kristin L / Lemay, Paul / O'Leary, Jessica / Schaefer, Todd / Verma, Pranshu / Toth, Ildiko / Block, Brian / Baker, Brett / Rothchild, Alissa / Lian, Jeffrey / Proudfoot, Jacqueline / Alvino, Donna Marie L / Vine, Seanna / Addo, Marylyn M / Allen, Todd M / Altfeld, Marcus / Henn, Matthew R / Le Gall, Sylvie / Streeck, Hendrik / Haas, David W / Kuritzkes, Daniel R / Robbins, Gregory K / Shafer, Robert W / Gulick, Roy M / Shikuma, Cecilia M / Haubrich, Richard / Riddler, Sharon / Sax, Paul E / Daar, Eric S / Ribaudo, Heather J / Agan, Brian / Agarwal, Shanu / Ahern, Richard L / Allen, Brady L / Altidor, Sherly / Altschuler, Eric L / Ambardar, Sujata / Anastos, Kathryn / Anderson, Ben / Anderson, Val / Andrady, Ushan / Antoniskis, Diana / Bangsberg, David / Barbaro, Daniel / Barrie, William / Bartczak, J / Barton, Simon / Basden, Patricia / Basgoz, Nesli / Bazner, Suzane / Bellos, Nicholaos C / Benson, Anne M / Berger, Judith / Bernard, Nicole F / Bernard, Annette M / Birch, Christopher / Bodner, Stanley J / Bolan, Robert K / Boudreaux, Emilie T / Bradley, Meg / Braun, James F / Brndjar, Jon E / Brown, Stephen J / Brown, Katherine / Brown, Sheldon T / Burack, Jedidiah / Bush, Larry M / Cafaro, Virginia / Campbell, Omobolaji / Campbell, John / Carlson, Robert H / Carmichael, J Kevin / Casey, Kathleen K / Cavacuiti, Chris / Celestin, Gregory / Chambers, Steven T / Chez, Nancy / Chirch, Lisa M / Cimoch, Paul J / Cohen, Daniel / Cohn, Lillian E / Conway, Brian / Cooper, David A / Cornelson, Brian / Cox, David T / Cristofano, Michael V / Cuchural, George / Czartoski, Julie L / Dahman, Joseph M / Daly, Jennifer S / Davis, Benjamin T / Davis, Kristine / Davod, Sheila M / DeJesus, Edwin / Dietz, Craig A / Dunham, Eleanor / Dunn, Michael E / Ellerin, Todd B / Eron, Joseph J / Fangman, John J W / Farel, Claire E / Ferlazzo, Helen / Fidler, Sarah / Fleenor-Ford, Anita / Frankel, Renee / Freedberg, Kenneth A / French, Neel K / Fuchs, Jonathan D / Fuller, Jon D / Gaberman, Jonna / Gallant, Joel E / Gandhi, Rajesh T / Garcia, Efrain / Garmon, Donald / Gathe, Joseph C / Gaultier, Cyril R / Gebre, Wondwoosen / Gilman, Frank D / Gilson, Ian / Goepfert, Paul A / Gottlieb, Michael S / Goulston, Claudia / Groger, Richard K / Gurley, T Douglas / Haber, Stuart / Hardwicke, Robin / Hardy, W David / Harrigan, P Richard / Hawkins, Trevor N / Heath, Sonya / Hecht, Frederick M / Henry, W Keith / Hladek, Melissa / Hoffman, Robert P / Horton, James M / Hsu, Ricky K / Huhn, Gregory D / Hunt, Peter / Hupert, Mark J / Illeman, Mark L / Jaeger, Hans / Jellinger, Robert M / John, Mina / Johnson, Jennifer A / Johnson, Kristin L / Johnson, Heather / Johnson, Kay / Joly, Jennifer / Jordan, Wilbert C / Kauffman, Carol A / Khanlou, Homayoon / Killian, Robert K / Kim, Arthur Y / Kim, David D / Kinder, Clifford A / Kirchner, Jeffrey T / Kogelman, Laura / Kojic, Erna Milunka / Korthuis, P Todd / Kurisu, Wayne / Kwon, Douglas S / LaMar, Melissa / Lampiris, Harry / Lanzafame, Massimiliano / Lederman, Michael M / Lee, David M / Lee, Jean M L / Lee, Marah J / Lee, Edward T Y / Lemoine, Janice / Levy, Jay A / Llibre, Josep M / Liguori, Michael A / Little, Susan J / Liu, Anne Y / Lopez, Alvaro J / Loutfy, Mono R / Loy, Dawn / Mohammed, Debbie Y / Man, Alan / Mansour, Michael K / Marconi, Vincent C / Markowitz, Martin / Marques, Rui / Martin, Jeffrey N / Martin, Harold L / Mayer, Kenneth Hugh / McElrath, M Juliana / McGhee, Theresa A / McGovern, Barbara H / McGowan, Katherine / McIntyre, Dawn / Mcleod, Gavin X / Menezes, Prema / Mesa, Greg / Metroka, Craig E / Meyer-Olson, Dirk / Miller, Andy O / Montgomery, Kate / Mounzer, Karam C / Nagami, Ellen H / Nagin, Iris / Nahass, Ronald G / Nelson, Margret O / Nielsen, Craig / Norene, David L / O'Connor, David H / Ojikutu, Bisola O / Okulicz, Jason / Oladehin, Olakunle O / Oldfield, Edward C / Olender, Susan A / Ostrowski, Mario / Owen, William F / Pae, Eunice / Parsonnet, Jeffrey / Pavlatos, Andrew M / Perlmutter, Aaron M / Pierce, Michael N / Pincus, Jonathan M / Pisani, Leandro / Price, Lawrence Jay / Proia, Laurie / Prokesch, Richard C / Pujet, Heather Calderon / Ramgopal, Moti / Rathod, Almas / Rausch, Michael / Ravishankar, J / Rhame, Frank S / Richards, Constance Shamuyarira / Richman, Douglas D / Rodes, Berta / Rodriguez, Milagros / Rose, Richard C / Rosenberg, Eric S / Rosenthal, Daniel / Ross, Polly E / Rubin, David S / Rumbaugh, Elease / Saenz, Luis / Salvaggio, Michelle R / Sanchez, William C / Sanjana, Veeraf M / Santiago, Steven / Schmidt, Wolfgang / Schuitemaker, Hanneke / Sestak, Philip M / Shalit, Peter / Shay, William / Shirvani, Vivian N / Silebi, Vanessa I / Sizemore, James M / Skolnik, Paul R / Sokol-Anderson, Marcia / Sosman, James M / Stabile, Paul / Stapleton, Jack T / Starrett, Sheree / Stein, Francine / Stellbrink, Hans-Jurgen / Sterman, F Lisa / Stone, Valerie E / Stone, David R / Tambussi, Giuseppe / Taplitz, Randy A / Tedaldi, Ellen M / Theisen, William / Torres, Richard / Tosiello, Lorraine / Tremblay, Cecile / Tribble, Marc A / Trinh, Phuong D / Tsao, Alice / Ueda, Peggy / Vaccaro, Anthony / Valadas, Emilia / Vanig, Thanes J / Vecino, Isabel / Vega, Vilma M / Veikley, Wenoah / Wade, Barbara H / Walworth, Charles / Wanidworanun, Chingchai / Ward, Douglas J / Warner, Daniel A / Weber, Robert D / Webster, Duncan / Weis, Steve / Wheeler, David A / White, David J / Wilkins, Ed / Winston, Alan / Wlodaver, Clifford G / van't Wout, Angelique / Wright, David P / Yang, Otto O / Yurdin, David L / Zabukovic, Brandon W / Zachary, Kimon C / Zeeman, Beth / Zhao, Meng

    Science (New York, N.Y.)

    2010  Volume 330, Issue 6010, Page(s) 1551–1557

    Abstract: Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a ... ...

    Abstract Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.
    MeSH term(s) Black or African American/genetics ; Alleles ; Amino Acids/physiology ; Antigen Presentation ; CD8-Positive T-Lymphocytes/immunology ; Cohort Studies ; Disease Progression ; Genes, MHC Class I ; Genome-Wide Association Study ; HIV Antigens/immunology ; HIV Infections/ethnology ; HIV Infections/genetics ; HIV Infections/immunology ; HIV Infections/virology ; HIV Long-Term Survivors ; HIV-1/immunology ; HLA-A Antigens/chemistry ; HLA-A Antigens/genetics ; HLA-A Antigens/immunology ; HLA-A Antigens/metabolism ; HLA-B Antigens/chemistry ; HLA-B Antigens/genetics ; HLA-B Antigens/immunology ; HLA-B Antigens/metabolism ; HLA-C Antigens/chemistry ; HLA-C Antigens/genetics ; HLA-C Antigens/immunology ; HLA-C Antigens/metabolism ; Haplotypes ; Hispanic or Latino/genetics ; Humans ; Immunity, Innate ; Logistic Models ; Models, Molecular ; Polymorphism, Single Nucleotide ; Protein Conformation ; Viral Load ; White People/genetics
    Chemical Substances Amino Acids ; HIV Antigens ; HLA-A Antigens ; HLA-B Antigens ; HLA-C Antigens
    Language English
    Publishing date 2010-11-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.1195271
    Database MEDical Literature Analysis and Retrieval System OnLINE

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