Evaluación de la unión de ocho péptidos del virus Sincitial respiratorio humano a los alelos MHC clase ii: HLA -DR1 Y HLA - DR4.

Desde que el virus sincitial respiratorio humano (VSRh) fue descubierto, no ha sido posible el desarrollo de profilaxis asequibles que permitan el control de la infección y que a su vez disminuyan los efectos sanitarios y el impacto económico generado por el mismo. El desarrollo de la respuesta inmu...

Full description

Autores:
Hernandez Gonzalez, Maritza
Herrera Gomez, Yury Katherine
Tipo de recurso:
Trabajo de grado de pregrado
Fecha de publicación:
2018
Institución:
Colegio Mayor de Cundinamarca
Repositorio:
Repositorio Colegio Mayor de Cundinamarca
Idioma:
spa
OAI Identifier:
oai:repositorio.unicolmayor.edu.co:unicolmayor/3569
Acceso en línea:
https://repositorio.unicolmayor.edu.co/handle/unicolmayor/3569
Palabra clave:
El Virus Sincitial Respiratorio
Patologías Neuromusculares
Bronquiolitis
Paramyxoviridae
Presentación de antígenos
Selección de Epítopes
Complejo MHC II/Péptido
Susceptibilidad HLA-DM
Algoritmos de unión a moléculas MHC clase II
Moléculas HLA-DR1 y DR4
Rights
closedAccess
License
Universidad Colegio Mayor de Cundinamarca, 2019
id UCOLMAYOR2_f1c9c154b9cafe8bd3730ae347074cd0
oai_identifier_str oai:repositorio.unicolmayor.edu.co:unicolmayor/3569
network_acronym_str UCOLMAYOR2
network_name_str Repositorio Colegio Mayor de Cundinamarca
repository_id_str
dc.title.spa.fl_str_mv Evaluación de la unión de ocho péptidos del virus Sincitial respiratorio humano a los alelos MHC clase ii: HLA -DR1 Y HLA - DR4.
title Evaluación de la unión de ocho péptidos del virus Sincitial respiratorio humano a los alelos MHC clase ii: HLA -DR1 Y HLA - DR4.
spellingShingle Evaluación de la unión de ocho péptidos del virus Sincitial respiratorio humano a los alelos MHC clase ii: HLA -DR1 Y HLA - DR4.
El Virus Sincitial Respiratorio
Patologías Neuromusculares
Bronquiolitis
Paramyxoviridae
Presentación de antígenos
Selección de Epítopes
Complejo MHC II/Péptido
Susceptibilidad HLA-DM
Algoritmos de unión a moléculas MHC clase II
Moléculas HLA-DR1 y DR4
title_short Evaluación de la unión de ocho péptidos del virus Sincitial respiratorio humano a los alelos MHC clase ii: HLA -DR1 Y HLA - DR4.
title_full Evaluación de la unión de ocho péptidos del virus Sincitial respiratorio humano a los alelos MHC clase ii: HLA -DR1 Y HLA - DR4.
title_fullStr Evaluación de la unión de ocho péptidos del virus Sincitial respiratorio humano a los alelos MHC clase ii: HLA -DR1 Y HLA - DR4.
title_full_unstemmed Evaluación de la unión de ocho péptidos del virus Sincitial respiratorio humano a los alelos MHC clase ii: HLA -DR1 Y HLA - DR4.
title_sort Evaluación de la unión de ocho péptidos del virus Sincitial respiratorio humano a los alelos MHC clase ii: HLA -DR1 Y HLA - DR4.
dc.creator.fl_str_mv Hernandez Gonzalez, Maritza
Herrera Gomez, Yury Katherine
dc.contributor.advisor.none.fl_str_mv Vargas Diaz, Luis Eduardo
dc.contributor.author.none.fl_str_mv Hernandez Gonzalez, Maritza
Herrera Gomez, Yury Katherine
dc.subject.lemb.none.fl_str_mv El Virus Sincitial Respiratorio
Patologías Neuromusculares
Bronquiolitis
Paramyxoviridae
topic El Virus Sincitial Respiratorio
Patologías Neuromusculares
Bronquiolitis
Paramyxoviridae
Presentación de antígenos
Selección de Epítopes
Complejo MHC II/Péptido
Susceptibilidad HLA-DM
Algoritmos de unión a moléculas MHC clase II
Moléculas HLA-DR1 y DR4
dc.subject.proposal.spa.fl_str_mv Presentación de antígenos
Selección de Epítopes
Complejo MHC II/Péptido
Susceptibilidad HLA-DM
Algoritmos de unión a moléculas MHC clase II
Moléculas HLA-DR1 y DR4
description Desde que el virus sincitial respiratorio humano (VSRh) fue descubierto, no ha sido posible el desarrollo de profilaxis asequibles que permitan el control de la infección y que a su vez disminuyan los efectos sanitarios y el impacto económico generado por el mismo. El desarrollo de la respuesta inmune adaptativa es uno de los campos que se ha venido explorando como alternativa a dicha problemática. Es así que, la identificación de péptidos antigénicos capaces de formar complejos MHC clase II HLA-DR/péptido resulta de gran importancia como base para la búsqueda de una vacuna segura y eficaz. En este trabajo de investigación se evaluó la capacidad de unión de ocho péptidos provenientes de las proteínas F, L, N, M, G y SH del VSRh para formar complejo HLA-DR/péptido con los alelos HLA- DR1 Y HLA-DR4 del complejo mayor de histocompatibilidad clase II. Para ello se empleó el algoritmo PROPRED y un ensayo de unión competitiva en presencia y ausencia de HLA-DM. Los resultados demuestran una correlación del 68% entre los datos teóricos y experimentales en ausencia de HLA-DM. Por otro lado, se observa que N-298 y L-962 son los péptidos de mayor afinidad por los alelos HLA-DR1 y HLA-DR4, indicando que pueden ser inmunógenos capaces de generar una respuesta inmunitaria efectiva contra el VSRh en individuos HLA-DR1 o HLA-DR4. De manera similar, los resultados sugieren que los péptidos SH-50, G1-58 Y L-832 pueden tener un papel similar a HLA-DM en la modulación de la formación del complejo MHC clase II/péptido.
publishDate 2018
dc.date.issued.none.fl_str_mv 2018-11
dc.date.accessioned.none.fl_str_mv 2021-10-27T20:55:22Z
dc.date.available.none.fl_str_mv 2021-10-27T20:55:22Z
dc.type.spa.fl_str_mv Trabajo de grado - Pregrado
dc.type.coar.spa.fl_str_mv http://purl.org/coar/resource_type/c_7a1f
dc.type.coarversion.spa.fl_str_mv http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.content.spa.fl_str_mv Text
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/bachelorThesis
dc.type.redcol.spa.fl_str_mv https://purl.org/redcol/resource_type/TP
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/publishedVersion
format http://purl.org/coar/resource_type/c_7a1f
status_str publishedVersion
dc.identifier.uri.none.fl_str_mv https://repositorio.unicolmayor.edu.co/handle/unicolmayor/3569
dc.identifier.barcode.none.fl_str_mv 58651
url https://repositorio.unicolmayor.edu.co/handle/unicolmayor/3569
identifier_str_mv 58651
dc.language.iso.spa.fl_str_mv spa
language spa
dc.relation.references.spa.fl_str_mv Simões, Eric A. F., Louis Bont, Paolo Manzoni, Brigitte Fauroux, Bosco Paes, Josep Figueras-Aloy, Paul A. Checchia, and Xavier Carbonell-Estrany. 2018. “Past, Present and Future Approaches to the Prevention and Treatment of Respiratory Syncytial Virus Infection in Children.” Infectious Diseases and Therapy 7 (1): 87–120. doi:10.1007/s40121-018-0188-z.
Singh, Harpreet, and G. P.S. Raghava. 2002. “ProPred: Prediction of HLA-DR Binding Sites.” Bioinformatics 17 (12): 1236–37. doi:10.1093/bioinformatics/17.12.1236.
Collins, Peter L., Rachel Fearns, and Barney S. Graham. 2013. “Respiratory Syncytial Virus: Virology, Reverse Genetics, and Pathogenesis of Disease.” Current Topics in Microbiology and Immunology 372: 3–38. doi:10.1007/978-3-642-38919-1-1.
Liang, Bo, Sonja Surman, Emerito Amaro-Carambot, Barbora Kabatova, Natalie Mackow, Matthias Lingemann, Lijuan Yang, et al. 2015. “Enhanced Neutralizing Antibody Response Induced by Respiratory Syncytial Virus Prefusion F Protein Expressed by a Vaccine Candidate.” Edited by T. S. Dermody. Journal of Virology 89 (18): 9499–9510. doi:10.1128/JVI.01373-15.
Kim, Joo Young, and Jun Chang. 2016. “In Hot Pursuit of the First Vaccine against Respiratory Syncytial Virus.” Yonsei Medical Journal. Yonsei University College of Medicine. doi:10.3349/ymj.2016.57.4.809.
Nair, Harish, D. James Nokes, Bradford D. Gessner, Mukesh Dherani, Shabir A. Madhi, Rosalyn J. Singleton, Katherine L. O’Brien, et al. 2010. “Global Burden of Acute Lower Respiratory Infections Due to Respiratory Syncytial Virus in Young Children: A Systematic Review and Meta-Analysis.” The Lancet 375 (9725): 1545–55. doi:10.1016/S0140-6736(10)60206-1
Walsh, Edward E. 2011. “Respiratory Syncytial Virus Infection in Adults.” Seminars in Respiratory and Critical Care Medicine 32 (4): 423–32. doi:10.1055/s-0031-1283282.
Paramore, L. Clark, Vincent Ciuryla, Gabrielle Ciesla, and Larry Liu. 2004. “Economic Impact of Respiratory Syncytial Virus-Related Illness in the US: An Analysis of National Databases.” PharmacoEconomics 22 (5): 275–84. doi:10.2165/00019053-200422050-00001.
Karime, L., Arango, O., & Durán, M. A. (2016). Virus sincitial respiratorio (vsr) en menores de 5 años, colombia, 2012 - 2016, 2012–2016. Retrieved from http://www.ins.gov.co/tramites-y-servicios/examenes-de-interés-en-salud-publica/Virologa/VSR en menores de 5 años.pdf
Instituto Nacional de Salud. 2017. semana epidemiológica número 50. https://www.ins.gov.co/buscador-eventos/BoletinEpidemiologico/2017%20Bolet%C3%ADn%20epidemiol%C3%B3gico%20semana%2051.pdf?fbclid=IwAR0ycbHjXH1fDNI8jg156t0heaVcUf-RN6upV8LQubI1VT0GDFn6L7taXLU
Instituto Nacional Salud. 2018. semana epidemiológica número 41. https://www.ins.gov.co/buscador-eventos/BoletinEpidemiologico/2018%20Bolet%C3%ADn%20epidemiol%C3%B3gico%20semana%2042.pdf?fbclid=IwAR27t1AfPANtFLqlqWn6caulmGE5n82cCyTGg__dvlqa4suT6W2RKlnuzYM
Barbosa, Juliana, Beatriz Parra, Alarcón Liliana, Flor Inés Quiñones, Eduardo López, and Manuel Antonio Franco. 2017. “Prevalencia y Periodicidad Del Virus Sincitial Respiratorio En Colombia.” Rev. Acad. Colomb. Cienc. Ex. Fis. Nat. 41 (161): 435–46. doi:http://dx.doi.org/10.18257/raccefyn.511.
Torres, Sandra Mónica Estupiñán, and Esperanza Trujillo Gama. 2004. “Complejo Mayor de Histocompatibilidad y Desarrollo de Vacunas.” NOVA. http://www.unicolmayor.edu.co/publicaciones/index.php/nova/article/view/24/47.
Sánchez-Trincado, J. L., Gomez-Perosanz, M., & Reche, P. A. (2017). Fundamentals and Methods for T- and B-Cell Epitope Prediction. Journal of Immunology Research. Hindawi Limited. https://doi.org/10.1155/2017/2680160
Arias-Murillo, Y., Castro-Jiménez, M., Ríos-Espinosa, M., López-Rivera, J., Echeverry-Coral, S., y Martínez-Nieto, O. (2011). Análisis de frecuencias alélicas, genotípicas y haplotípicas de HLA-A, HLA-B, HLA-DRB1 en la población colombiana. Colombia MéDica, 41 (4), 336-343. http://colombiamedica.univalle.edu.co/index.php/comedica/article/view/725/1186.
Rodríguez Libia M, Giraldo Mabel C, García Natalia, Velásquez Laura, París Sara C, Álvarez Cristiam M et al . Frecuencias alélicas, genotípicas y haplotípicas HLA-A, HLA-B, HLA-DRB1 en donantes fallecidos, Medellín, Colombia. Biomédica [Internet]. 2007 Dec [cited 2018 Oct 27]; 27( 4 ): 537-547. Available from: http://www.scielo.org.co/scielo.php?script=sci_arttext&pid=S0120-41572007000400009&lng=en.
Painter, Corrie A, and Lawrence J Stern. 2011. “Structural Insights Into HLA-DM Mediated MHC II Peptide Exchange.” Current Topics in Biochemical Research 13 (2): 39–55. doi:10.1016/j.biotechadv.2011.08.021.Secreted.
Vargas L.E. et al. (2003) MHC allele-specific binding of a malaria peptide makes it become promiscuous on fitting a glycine residue into pocket 6. Biochemical and Biophysical Research Communications 307 148–156. doi:10.1016/S0006-291X(03)01129-X
Day, Cheryl L, Nilufer P Seth, Michaela Lucas, Heiner Appel, Laurent Gauthier, Georg M Lauer, Gregory K Robbins, et al. 2003. “Ex Vivo Analysis of Human Memory CD4 T Cells Specific for Hepatitis C Virus Using MHC Class II Tetramers” 112 (6): 831–42. doi:10.1172/JCI200318509
Yu, Yang, Dongdong Jin, Shizong Hu, Yan Zhang, Xiaojing Zheng, Jianhua Zheng, Mingfeng Liao, et al. 2015. “A Novel Tuberculosis Antigen Identified from Human Tuberculosis Granulomas.” Molecular & Cellular Proteomics 14 (4): 1093–1103. doi:10.1074/mcp.M114.045237.
Yin, L., Maben, Z., Becerra, A., & Stern, L. J. (2015). Evaluating the role of HLA-DM in MHC II-peptide association reactions. Journal of Immunology (Baltimore, Md. : 1950), 195(2), 706–716. http://doi.org/10.4049/jimmunol.1403190
Hurwitz, Julia L. 2011. “Respiratory Syncytial Virus Vaccine Development.” Expert Review of Vaccines. doi:10.1586/erv.11.120.
Chanock, Robert M, Keith Jensen, and Robert H Parrott. 1969. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine1- 2- 89(4): 422–34.
Graham, Barney S. 2016. “Vaccines against Respiratory Syncytial Virus: The Time Has Finally Come.” Vaccine 34 (30). Elsevier Ltd: 3535–41. doi:10.1016/j.vaccine.2016.04.083.
Higgins, Deborah, Carrie Trujillo, and Cheryl Keech. 2016. “Advances in RSV Vaccine Research and Development - A Global Agenda.” Vaccine 34 (26). Elsevier Ltd: 2870–75. doi:10.1016/j.vaccine.2016.03.109.
Rudraraju, R., Jones, B. G., Sealy, R., Surman, S. L., & Hurwitz, J. L. (2013). Respiratory syncytial virus: current progress in vaccine development. Viruses, 5(2), 577–94. https://doi.org/10.3390/v5020577
J. Díez y V. Planelles.2011. Vacuna frente al virus respiratorio sincitial. An Pediatr Contin; 9(1):64-8. http://appswl.elsevier.es/watermark/ctl_servlet?_f=10&pident_articulo=80000599&pident_usuario=0&pcontactid=&pident_revista=51&ty=130&accion=L&origen=apccontinuada&web=www.apcontinuada.com&lan=es&fichero=v9n1a499pdf001.pdf&anuncioPdf=ERROR_publi_pdf&fbclid=IwAR0c_jnEkHdXA1XLCl83ySN4-10ZkQuVYBNHDKfIaio2nmtrgL90TjlBjq8
Rodríguez Libia M, Giraldo Mabel C, García Natalia, Velásquez Laura, París Sara C, Álvarez Cristiam M et al . Frecuencias alélicas, genotípicas y haplotípicas HLA-A, HLA-B, HLA-DRB1 en donantes fallecidos, Medellín, Colombia. Biomédica [Internet]. 2007 Dec [cited 2018 Oct 27]; 27( 4 ): 537-547. Available from: http://www.scielo.org.co/scielo.php?script=sci_arttext&pid=S0120-41572007000400009&lng=en
Zhang, Lianming, Yiqing Chen, Hau San Wong, Shuigeng Zhou, Hiroshi Mamitsuka, and Shanfeng Zhu. 2012. “TepitopePan: Extending Tepitope for Peptide Binding Prediction Covering over 700 Hla-Dr Molecules.” PLoS ONE 7 (2). doi:10.1371/journal.pone.0030483
Singh, Harpreet, and G. P.S. Raghava. 2002. “ProPred: Prediction of HLA-DR Binding Sites.” Bioinformatics 17 (12): 1236–37. doi:10.1093/bioinformatics/17.12.1236.
Nielsen, Morten, Ole Lund, Soren Buus, and Claus Lundegaard. 2010. “MHC Class II Epitope Predictive Algorithms.” Immunology. doi:10.1111/j.1365-2567.2010.03268.x.
Chaves, F. A., Lee, A. H., Nayak, J., Richards, K. A., & Sant, A. J. (2012). The utility and limitations of current web-available algorithms to predict peptides recognized by CD4 T cells in response to pathogen infection . Journal of Immunology (Baltimore, Md. : 1950), 188(9), 4235–4248. doi:10.4049/jimmunol.1103640.
Marek Wieczorek, Esam T, Front Immunol. 2017; 8: 292. Published online 2017 Mar 17,Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355494/
Secretaria distrital de salud.Curso basico de medicina transfusional.editorial maldonado SA
Deborah A. Lipski, Rémi Dewispelaere,MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis J Neuroinflammation. 2017; 14: 136
Brown, J H, T S Jardetzky, J C Gorga, L J Stern, R G Urban, J L Strominger, and D C Wiley. 1993. “Three-Dimensional Structure of the Human Class II Histocompatibility Antigen HLA-DR1.” Nature 364 (6432): 33–39. doi:10.1038/364033a0
William Sherwin, Lars, Bejder, Celine Frère, Michael Krützen, Janet Mann, Tracey Rogers. Fitness & major histocompatibility complex diversity of two bottlenose dolphin populations DOI: 10.13140/RG.2.1.1804.2480.
Painter, Corrie A, and Lawrence J Stern. 2011. “Structural Insights Into HLA-DM Mediated MHC II Peptide Exchange.” Current Topics in Biochemical Research 13 (2): 39–55. doi:10.1016/j.biotechadv.2011.08.021.Secreted.
Bian, Hongjin, John F. Reidhaar-Olson, and Juergen Hammer. 2003. “The Use of Bioinformatics for Identifying Class II-Restricted T-Cell Epitopes.” Methods 29 (3). Academic Press Inc.: 299–309. doi:10.1016/S1046-2023(02)00352-3.
Mecanismos de procesamiento y presentación antigénica en autoinmunidad. Universidad Autónoma de Barcelona, Bellaterra Mayo 2017
Braendstrup P, Mortensen BK, Justesen S, Østerby T, Rasmussen M, et al. (2014) Identification and HLA-Tetramer-Validation of Human CD4+ and CD8+ T Cell Responses against HCMV Proteins IE1 and IE2. PLoS ONE 9(4): doi:10.1371/journal.pone.0094892
Blazekovic, F., Odukoya, D., Butler, S. N., Mauro, J. A., Ramsamooj, M., Puleo, E. Blanck, G. (2016). HLA-DR peptide occupancy can be regulated with a wide variety of small molecules. Human Vaccines and Immunotherapeutics, 12(3), 593–598. https://doi.org/10.1080/21645515.2015.1089370
Steven G.E. Marsh, Peter Parham, Linda D. Barber. THE HLA. FactsBook Academic press.92101-4495. USA. Capítulo 7. Pag.41-73.
Rammensee, H G. 1995. “Chemistry of Peptides Associated with MHC Class I and Class II Molecules.” Curr Opin Immunol 7 (1): 85–96. doi:0952-7915(95)80033-6.
Matsumura, M, D H Fremont, P a Peterson, and I a Wilson. 1992. “Emerging Principles for the Recognition of Peptide Antigens by MHC Class I Molecules.” Science 257 (1991): 927–34.
Scott Southwood, John Sidney, Akihiro Kondo, Marie-France del Guercio, Ettore Appella, Stephen Hoffman, Ralph T. Kubo, Robert W. Chesnut, Howard M Grey and Alessandro Sette. 1998, Several Common HLA-DR Types Share Largely Overlapping Peptide Binding Repertoires J Immunol. J Immunol 1998; 160:3363-3373; http://www.jimmunol.org/content/160/7/3363
HLA-DRB1 major histocompatibility complex, class II, DR beta Gene ID: 3123.
Dominguez Horta, María, y Noraylis Lorenzo Pérez, y Ariana Barbera Betancourt, y María Victoria Hernández Cuellar, y Ana María Torres Lima, y M. Nazabal, y H. Camacho, e Isabel María Hernández Cuellar, y Neisy Ortiz, y V. Morera, y Ramón Gabriel Padrón Palomares. 2006. "Caracterización de Moléculas HLA tipo II y evaluación de citocinas en pacientes cubanos con Artritis Reumatoide". Revista Cubana de Reumatología 8 (9-10): 43-51
Júlia Kurkó Et al. 2013 Genetics of Rheumatoid Arthritis:A Comprehensive Review. Clin Rev Allergy Immunol; 45(2): 170–179. doi:10.1007/s12016-012-8346-7.
Albert J. C Zaja,Michael P. Manns,2010,Advances in the Diagnosis, Pathogenesis, and Management of Autoimmune Hepatitis,GASTROENTEROLOGY ;139:58 –72,doi:10.1053/j.gastro.2010.04.053
Kareem Sassi ,Jose M. Nieto ,Sammy Saab 2015,– Trasplante de Hepatitis Autoinmune, páginas 174-188, Capítulo 15
Pos, W. et al. (2012) Crystal structure of the HLA-DM–HLA-DR1 complex defines mechanisms for rapid peptide selection. Cell 151, 1557–1568
Yin, Liusong, and Lawrence J. Stern. 2013. “HLA-DM Focuses on Conformational Flexibility Around P1 Pocket to Catalyze Peptide Exchange.” Frontiers in Immunology 4. doi:10.3389/fimmu.2013.00336
Liusong Yin, Zachary J. Maben, Aniuska Becerra and Lawrence J. Stern J Immunol July 15, 2015, 195 (2) 706-716; Evaluating the Role of HLA-DM in MHC Class II–Peptide Association Reactions DOI: https://doi.org/10.4049/jimmunol.1403190
Gilca, Rodica, Gaston De Serres, Mireille Tremblay, Marie-Louise Vachon, Eric Leblanc, Michel G Bergeron, Pierre Dery, and Guy Boivin. 2006. “Distribution and Clinical Impact of Human Respiratory Syncytial Virus Genotypes in Hospitalized Children over 2 Winter Seasons.” The Journal of Infectious Diseases 193: 54–58. doi:10.1086/498526.
Vandini, Silvia, Carlotta Biagi, and Marcello Lanari. 2017. “Respiratory Syncytial Virus: The Influence of Serotype and Genotype Variability on Clinical Course of Infection.” International Journal of Molecular Sciences. MDPI AG. doi:10.3390/ijms18081717.
Johansson, Cecilia. 2016. “Respiratory Syncytial Virus Infection: An Innate Perspective.” F1000Research 5 (December): 2898. doi:10.12688/f1000research.9637.1.
Melero, José A., Vicente Mas, and Jason S. McLellan. 2017. “Structural, Antigenic and Immunogenic Features of Respiratory Syncytial Virus Glycoproteins Relevant for Vaccine Development.” Vaccine 35 (3). Elsevier Ltd: 461–68. doi:10.1016/j.vaccine.2016.09.045.
Griffiths C, Drews SJ, Marchant DJ. 2017. Respiratory syncytial virus: infection, detection, and new options for prevention and treatment. Clin Microbiol Rev 30:277–319. https://doi.org/10.1128/CMR.00010-16
Emma Rey-Jurado and Alexis M. Kalergis.2017. Immunological Features of Respiratory Syncytial Virus-Caused Pneumonia—Implications for Vaccine Design.Int. J. Mol. Sci., 18, 556; doi:10.3390/ijms18030556
Nicolás M. S. Gálvez, Jorge A. Soto, Alexis M. Kalergis,2017, New Insights Contributing to the Development of Effective Vaccines and Therapies to Reduce the Pathology Caused by hRSV. Int. J. Mol. Sci., 18, 1753; doi:10.3390/ijms18081753.
Alexander Kotelkin, Igor M. Belyakov, Lijuan Yang, Jay A. Berzofsky, Peter L. Collins, and Alexander Bukreyev , 2006, The NS2 Protein of Human Respiratory Syncytial Virus Suppresses the Cytotoxic T-Cell Response as a Consequence of Suppressing the Type I Interferon Response. JOURNAL OF VIROLOGY,, p. 5958–5967 Vol. 80, doi:10.1128/JVI.00181-06.
Claire P Straub, Wei-Har Lau, Faith M Preston, Madeleine J Headlam, Jeffery J Gorman, Peter L Collins and Kirsten M Spann,2011, Mutation of the elongin C binding domain of human respiratory syncytial virus non-structural protein 1 (NS1) results in degradation of NS1 and attenuation of the virus. Straub et al. Virology Journal, 8:252 https://doi.org/10.1186/1743-422X-8-252
Hastie M et al. 2012 The Human Respiratory Syncytial Virus Nonstructural Protein 1 Regulates Type I and Type II Interferon Pathways.Molecular & Cellular Proteomics 11: 10.1074/ mcp.M111.015909, 108 –127
Peter L. Collins. Rachel Fearns. Barney S. Graham,2013, espinoza Curr Top Microbiol Immunol. 2013; 372: 3–38. Doi:10.1007/978-3-642-38919-1_1.
Céspedes P et al. .2014,Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells. PNAS,DOI:10.1073/pnas.1400760111.
Ruchira Mitra, Pradyumna Baviskar, Rebecca R, 2012, Duncan-Decocq, Darshna Patel, and Antonius G. P. Oomens. The Human Respiratory Syncytial Virus Matrix Protein Is Required for Maturation of Viral Filaments. Journal of Virology p. 4432–4443. 2012.DOI:10.1128/JVI.06744-11
Ghildyal, Reena, Adeline Ho, and David A. Jans. 2006. “Central Role of the Respiratory Syncytial Virus Matrix Protein in Infection.” FEMS Microbiology Reviews. doi:10.1111/j.1574-6976.2006.00025.x.
Liang, Bo, Sonja Surman, Emerito Amaro-Carambot, Barbora Kabatova, Natalie Mackow, Matthias Lingemann, Lijuan Yang, et al. 2015. “Enhanced Neutralizing Antibody Response Induced by Respiratory Syncytial Virus Prefusion F Protein Expressed by a Vaccine Candidate.”. Journal of Virology 89 (18): 9499–9510. doi:10.1128/JVI.01373-15.
Rossey, Iebe, Jason S. McLellan, Xavier Saelens, and Bert Schepens. 2017. “Clinical Potential of Prefusion RSV F-Specific Antibodies.” Trends in Microbiology. doi:10.1016/j.tim.2017.09.009.
Gagliardi T, B, Criado M, F, Proença-Módena J, L, Saranzo A, M, Iwamoto M, A, de Paula F, E, Cardoso R, S, Delcaro L, S, Silva M, L, Câmara A, A, Arruda E: Syncytia Induction by Clinical Isolates of Human Respiratory Syncytial Virus A. Intervirology 2017;60:56-60. doi: 10.1159/000480014
Carter, Stephen D., Kyle C. Dent, Elizabeth Atkins, Toshana L. Foster, Mark Verow, Petra Gorny, Mark Harris, et al. 2010. “Direct Visualization of the Small Hydrophobic Protein of Human Respiratory Syncytial Virus Reveals the Structural Basis for Membrane Permeability.” FEBS Letters 584 (13): 2786–90. doi:10.1016/j.febslet.2010.05.006.
Fuentes, S., K. C. Tran, P. Luthra, M. N. Teng, and B. He. 2007. “Function of the Respiratory Syncytial Virus Small Hydrophobic Protein.” Journal of Virology 81 (15): 8361–66. doi:10.1128/JVI.02717-06.
Schepens, Bert, Koen Sedeyn, Liesbeth Vande Ginste, Sarah De Baets, Michael Schotsaert, Kenny Roose, Lieselot Houspie, et al. 2014. “Protection and Mechanism of Action of a Novel Human Respiratory Syncytial Virus Vaccine Candidate Based on the Extracellular Domain of Small Hydrophobic Protein.” EMBO Mol Med 6: 1436–54. doi:10.15252/emmm.201404005.
Schepens, Bert. 2015. “Small Hydrophobic Protein of Respiratory Syncytial Virus as a Novel Vaccine Antigen.” Immunotherapy 7: 203–6. doi:10.2217/imt.15.11.
Melero, José A., Vicente Mas, and Jason S. McLellan. 2017. “Structural, Antigenic and Immunogenic Features of Respiratory Syncytial Virus Glycoproteins Relevant for Vaccine Development.” Vaccine 35 (3). Elsevier Ltd: 461–68. doi:10.1016/j.vaccine.2016.09.045.
Boyoglu-Barnum S, Todd SO, Meng J, Barnum TR, Chirkova T, Haynes LM, Jadhao SJ, Tripp RA, Oomens AG, Moore ML, Anderson LJ. 2017. Mutating the CX3C motif in the G protein should make a live respiratory syncytial virus vaccine safer and more effective. J Virol 91:e02059-16. https:// doi.org/10.1128/JVI.02059-16.
Chirkova, Tatiana, Songbai Lin, Antonius G P Oomens, Kelsey A Gaston, Seyhan Boyoglu-Barnum, Jia Meng, Christopher C Stobart, et al. 2015. “CX3CR1 Is an Important Surface Molecule for Respiratory Syncytial Virus Infection in Human Airway Epithelial Cells.” The Journal of General Virology 96 (9). Microbiology Society: 2543–56. doi:10.1099/vir.0.000218.
Fix, J., Galloux, M., Blondot, M. L., & Eléouët, J. F. (2011). The insertion of fluorescent proteins in a variable region of respiratory syncytial virus L polymerase results in fluorescent and functional enzymes but with reduced activities. The open virology journal, 5, 103-8
Castagné, Nathalie, Alexandra Barbier, Julie Bernard, Human Rezaei, Jean Claude Huet, Céline Henry, Bruno Da Costa, and Jean François Eléouët. 2004. “Biochemical Characterization of the Respiratory Syncytial Virus P-P and P-N Protein Complexes and Localization of the P Protein Oligomerization Domain.” Journal of General Virology 85 (6): 1643–53. doi:10.1099/vir.0.79830-0.
Espinoza J, Bueno S, Riedel C, Kalergis A. 2014 Induction of protective effector immunity to prevent pathogenesis caused by the respiratory syncytial virus. Implications on therapy and vaccine designImmunology, 143, 1–12. doi:10.1111/imm.12313
Rey-Jurado, E., & Kalergis, A. M. (2017). Immunological Features of Respiratory Syncytial Virus-Caused Pneumonia-Implications for Vaccine Design. International journal of molecular sciences, 18(3), 556. doi:10.3390/ijms18030556
Mylene Corzo-López y Odalys Valdés-Ramírez.* El virus sincitial respiratorio humano: una panorámica, Revista CENIC Ciencias Biológicas, Vol. 44, No. 2, mayo-agosto, 2013.http://www.redalyc.org/pdf/1812/181227534005.pdf
Chartrand, C., Tremblay, N., Renaud, C., & Papenburg, J. (2015). Diagnostic Accuracy of Rapid Antigen Detection Tests for Respiratory Syncytial Virus Infection: Systematic Review and Meta-analysis. Journal of clinical microbiology, 53(12), 3738-49.
Pilie, P., W. A. Werbel, J. Riddell, X. Shu, D. Schaubel, and K. S. Gregg. 2015. “Adult Patients with Respiratory Syncytial Virus Infection: Impact of Solid Organ and Hematopoietic Stem Cell Transplantation on Outcomes.” Transplant Infectious Disease 17 (4). Blackwell Publishing Inc.: 551–57. doi:10.1111/tid.12409.
Paes, Bosco A., Ian Mitchell, Anna Banerji, Krista L. Lanctôt, and Joanne M. Langley. 2011. “A Decade of Respiratory Syncytial Virus Epidemiology and Prophylaxis: Translating Evidence into Everyday Clinical Practice.” Canadian Respiratory Journal. Hindawi Limited. doi:10.1155/2011/493056.
Bont, Louis, Paul A. Checchia, Brigitte Fauroux, Josep Figueras-Aloy, Paolo Manzoni, Bosco Paes, Eric A.F. and Xavier Carbonell-Estrany. 2016. “Defining the Epidemiology and Burden of Severe Respiratory Syncytial Virus Infection Among Infants and Children in Western Countries.” Infectious Diseases and Therapy. Springer Healthcare. doi:10.1007/s40121-016-0123-0
Robbie, G. J., Criste, R., Dall'acqua, W. F., Jensen, K., Patel, N. K., Losonsky, G. A., & Griffin, M. P. (2013). A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrobial agents and chemotherapy, 57(12), 6147-53.
Graham BS,(2016) , Vaccines against respiratory syncytial virus: The time has finally come. Vaccine , http://dx.doi.org/10.1016/j.vaccine.2016.04.083
J.A. Bastarache, T. Koyama, N.E Wickersham, and L.B. Ware, 2014 ;. Validation of a multiplex electrochemiluminescent immunoassay platform in human and mouse samples.J Immunol Methods, doi:10.1016/j.jim.2014.04.006.
Rojas-Caraballo, J., López-Abán, J., Pérez Del Villar, L., Vizcaíno, C., Vicente, B., Fernández-Soto, P., Muro, A. (2014). In vitro and in vivo studies for assessing the immune response and protection-inducing ability conferred by Fasciola hepatica-derived synthetic peptides containing B- and T-cell epitopes. PLoS ONE, 9(8). https://doi.org/10.1371/journal.pone.0105323
Creech AL, Ting YS,2018,The Role of Mass Spectrometry and Proteogenomics in the Advancement of HLA Epitope Prediction.Proteomics. doi: 10.1002/pmic.201700259.
L.E VARGAS,2011, Influencia de HLA-DM en la estabilidad del complejo formado entre la molécula HLA-DR4 y un péptido de la proteína CS de P. falciparum. Universidad Nacional Facultad de Medicina, http://bdigital.unal.edu.co/8745/1/597342.2011.pdf
Yin, Liusong, Peter Trenh, Abigail Guce, Marek Wieczorek, Sascha Lange, Jana Sticht, Wei Jiang, et al. 2014. “Susceptibility to HLA-DM Protein Is Determined by a Dynamic Conformation of Major Histocompatibility Complex Class II Molecule Bound with Peptide.” Journal of Biological Chemistry 289 (34). American Society for Biochemistry and Molecular Biology Inc.: 23449–64. doi:10.1074/jbc.M114.585539
Yin, L., J. M. Calvo-Calle, O. Dominguez-Amorocho, and L. J. Stern. 2012. “HLA-DM Constrains Epitope Selection in the Human CD4 T Cell Response to Vaccinia Virus by Favoring the Presentation of Peptides with Longer HLA-DM-Mediated Half-Lives.” The Journal of Immunology 189 (8): 3983–94. doi:10.4049/jimmunol.1200626.
Hall, Frances C., Joshua D. Rabinowitz, Robert Busch, Kevin C. Visconti, Michael Belmares, Namrata S. Patil, Andrew P. Cope, et al. 2002. “Relationship between Kinetic Stability and Immunogenicity of HLA- DR4/Peptide Complexes.” European Journal of Immunology 32 (3): 662–70. doi:10.1002/1521-4141(200203)32:3<662::AID-IMMU662>3.0.CO;2-5.
Lin, Hong Huang, Guang Lan Zhang, Songsak Tongchusak, Ellis L. Reinherz, and Vladimir Brusic. 2008. “Evaluation of MHC-II Peptide Binding Prediction Servers: Applications for Vaccine Research.” In BMC Bioinformatics. Vol. 9. doi:10.1186/1471-2105-9-S1-S22
Achal Pashine, Robert Busch, 2003, Interaction of HLA-DR with an Acidic Face of HLA-DM Disrupts Sequence-Dependent Interactions with Peptides. Immunity, Vol. 19, 183–192,DOI:https://doi.org/10.1016/S1074-7613(03)00200-0.
Viviana Marin-Esteban, Kirsten Falk,Chemical ,2004,Analogues of HLA-DM Can Induce a Peptide-receptive State in HLA-DR Molecules. JBC Papers in Press, DOI 10.1074/jbc.M407598200.
Alvarado A, Tenorio G.V R, Aguilar S,A, Sandoval T,AH.2006.Promesas y limitaciones de las vacunas antigénicas. Revista Mexicana de ciencias Farmacéuticas. [Internet]:37(2):26-37. http://www.redalyc.org/pdf/579/57937205.pdf
dc.rights.spa.fl_str_mv Universidad Colegio Mayor de Cundinamarca, 2019
dc.rights.uri.spa.fl_str_mv https://creativecommons.org/licenses/by-nc-sa/4.0/
dc.rights.accessrights.spa.fl_str_mv info:eu-repo/semantics/closedAccess
dc.rights.creativecommons.spa.fl_str_mv Atribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0)
dc.rights.coar.spa.fl_str_mv http://purl.org/coar/access_right/c_14cb
rights_invalid_str_mv Universidad Colegio Mayor de Cundinamarca, 2019
https://creativecommons.org/licenses/by-nc-sa/4.0/
Atribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0)
http://purl.org/coar/access_right/c_14cb
eu_rights_str_mv closedAccess
dc.format.extent.spa.fl_str_mv 95p.
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv Universidad Colegio Mayor de Cundinamarca
dc.publisher.faculty.spa.fl_str_mv Facultad de Ciencias de la Salud
dc.publisher.place.spa.fl_str_mv Bogotá D.C
dc.publisher.program.spa.fl_str_mv Bacteriología y Laboratorio Clínico
institution Colegio Mayor de Cundinamarca
bitstream.url.fl_str_mv https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/1/Cartas%20derechos%20de%20autor.pdf
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/2/Proyecto%20de%20grado..pdf
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/3/Proyecto%20de%20Grado.pdf
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/4/license.txt
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/5/Cartas%20derechos%20de%20autor.pdf.txt
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/7/Proyecto%20de%20grado..pdf.txt
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/9/Proyecto%20de%20Grado.pdf.txt
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/6/Cartas%20derechos%20de%20autor.pdf.jpg
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/8/Proyecto%20de%20grado..pdf.jpg
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/10/Proyecto%20de%20Grado.pdf.jpg
bitstream.checksum.fl_str_mv 7f85c42e8331618a76f9c7fa2491f459
67ea10eb9569e0133c83c4baec9ddc65
6f81e2856e715de46bc00e1cb62aabe4
2f9959eaf5b71fae44bbf9ec84150c7a
d3055369a061017d1d1bd3375129a6df
6d720b4218f8a01e3dcb6ec334a891e7
b2068747021ce9804b5a182532c91482
2024383a0ea8e4f51d1962b0a5a3b24a
73861401e49b8680c021515d0fc12c1b
973a00fad391c3a95ece74134131e8c9
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
MD5
MD5
MD5
MD5
MD5
MD5
repository.name.fl_str_mv Biblioteca Digital Unicolmayor
repository.mail.fl_str_mv repositorio@unicolmayor.edu.co
_version_ 1812210051741384704
spelling Vargas Diaz, Luis Eduardo156024c5f7a4105ae18c184523976d47Hernandez Gonzalez, Maritzac77547debd535cf0a2bdc9e8df968172Herrera Gomez, Yury Katherine39678808f1d8c5589884d05e766e5f5a2021-10-27T20:55:22Z2021-10-27T20:55:22Z2018-11https://repositorio.unicolmayor.edu.co/handle/unicolmayor/356958651Desde que el virus sincitial respiratorio humano (VSRh) fue descubierto, no ha sido posible el desarrollo de profilaxis asequibles que permitan el control de la infección y que a su vez disminuyan los efectos sanitarios y el impacto económico generado por el mismo. El desarrollo de la respuesta inmune adaptativa es uno de los campos que se ha venido explorando como alternativa a dicha problemática. Es así que, la identificación de péptidos antigénicos capaces de formar complejos MHC clase II HLA-DR/péptido resulta de gran importancia como base para la búsqueda de una vacuna segura y eficaz. En este trabajo de investigación se evaluó la capacidad de unión de ocho péptidos provenientes de las proteínas F, L, N, M, G y SH del VSRh para formar complejo HLA-DR/péptido con los alelos HLA- DR1 Y HLA-DR4 del complejo mayor de histocompatibilidad clase II. Para ello se empleó el algoritmo PROPRED y un ensayo de unión competitiva en presencia y ausencia de HLA-DM. Los resultados demuestran una correlación del 68% entre los datos teóricos y experimentales en ausencia de HLA-DM. Por otro lado, se observa que N-298 y L-962 son los péptidos de mayor afinidad por los alelos HLA-DR1 y HLA-DR4, indicando que pueden ser inmunógenos capaces de generar una respuesta inmunitaria efectiva contra el VSRh en individuos HLA-DR1 o HLA-DR4. De manera similar, los resultados sugieren que los péptidos SH-50, G1-58 Y L-832 pueden tener un papel similar a HLA-DM en la modulación de la formación del complejo MHC clase II/péptido.RESUMEN12 INTRODUCCIÓN13 1. OBJETIVOS15 1.1 OBJETIVO GENERAL15 1.2 OBJETIVOS ESPECÍFICOS15 2. JUSTIFICACIÓN16 3. ANTECEDENTES18 4. MARCO TEÓRICO23 4.1 Moléculas MHC clase II: Estructura, función y características de la unión HLA/ péptido23 4.2 Virus sincitial respiratorio humano28 4.2.1 Proteínas no estructurales31 4.2.2 Proteína N31 4.2.3 Proteína M32 4.2.4 Proteína F33 4.2.5 Proteína SH (Small Hydrophobic36 4.2.6 Proteína G38 4.2.7 Proteína L40 4.2.8 Proteína P42 4.3 Respuesta inmune frente al Virus Sincitial Respiratorio Humano43 4.4 Manifestaciones clínicas y diagnóstico del VSRh44 4.5 Epidemiologia44 4.6 Tratamiento y protección frente al VSRh46 4.7 Ensayos inmunoenzimáticos (ELISA48 4.8 Algoritmo predictivo RAGHAVA-PROPRED48 5. DISEÑO METODOLÓGICO50 5.1 Moléculas MHC clase II y HLA-DM50 5.2 Péptido control biotinilado: Hemaglutinina (HA) 306-31850 5.3 Péptidos del virus sincitial respiratorio51 5.4 Determinación del porcentaje de unión empleando el algoritmo PROPRED53 7 5.5 Ensayo de unión MHC clase II/ Péptidos54 5.6 Ensayo de Unión MHC clase II/ Péptidos / HLA-DM56 5.7 Determinación del porcentaje de unión relativo MHC clase II/péptido56 6. RESULTADOS57 6.1 Determinación del porcentaje de unión de los péptidos F-137, L-962, N-298, L-832, L-449, M-68, G1-58 a los alelos HLA-DRB1* 0101 y HLA-DRB1*0401 empleando el algoritmo PROPRED57 6.2 Determinación experimental de los porcentajes de unión relativos de péptidos del VSRh a moléculas HLA-DR1 Y HLA-DR4 en presencia y ausencia de HLA-DM59 6.3 Comparación del porcentaje de unión de cada péptido con HLA-DR1 y HLA- DR4 en presencia y ausencia de HLA-DM63 7. DISCUSIÓN67 8. CONCLUSIONES73 RECOMENDACIONES76 REFERENCIAS77 ANEXOS90PregradoBacteriólogo(a) y Laboratorista Clínico95p.application/pdfspaUniversidad Colegio Mayor de CundinamarcaFacultad de Ciencias de la SaludBogotá D.CBacteriología y Laboratorio ClínicoUniversidad Colegio Mayor de Cundinamarca, 2019https://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/closedAccessAtribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0)http://purl.org/coar/access_right/c_14cbEvaluación de la unión de ocho péptidos del virus Sincitial respiratorio humano a los alelos MHC clase ii: HLA -DR1 Y HLA - DR4.Trabajo de grado - Pregradohttp://purl.org/coar/resource_type/c_7a1fhttp://purl.org/coar/version/c_970fb48d4fbd8a85Textinfo:eu-repo/semantics/bachelorThesishttps://purl.org/redcol/resource_type/TPinfo:eu-repo/semantics/publishedVersionSimões, Eric A. F., Louis Bont, Paolo Manzoni, Brigitte Fauroux, Bosco Paes, Josep Figueras-Aloy, Paul A. Checchia, and Xavier Carbonell-Estrany. 2018. “Past, Present and Future Approaches to the Prevention and Treatment of Respiratory Syncytial Virus Infection in Children.” Infectious Diseases and Therapy 7 (1): 87–120. doi:10.1007/s40121-018-0188-z.Singh, Harpreet, and G. P.S. Raghava. 2002. “ProPred: Prediction of HLA-DR Binding Sites.” Bioinformatics 17 (12): 1236–37. doi:10.1093/bioinformatics/17.12.1236.Collins, Peter L., Rachel Fearns, and Barney S. Graham. 2013. “Respiratory Syncytial Virus: Virology, Reverse Genetics, and Pathogenesis of Disease.” Current Topics in Microbiology and Immunology 372: 3–38. doi:10.1007/978-3-642-38919-1-1.Liang, Bo, Sonja Surman, Emerito Amaro-Carambot, Barbora Kabatova, Natalie Mackow, Matthias Lingemann, Lijuan Yang, et al. 2015. “Enhanced Neutralizing Antibody Response Induced by Respiratory Syncytial Virus Prefusion F Protein Expressed by a Vaccine Candidate.” Edited by T. S. Dermody. Journal of Virology 89 (18): 9499–9510. doi:10.1128/JVI.01373-15.Kim, Joo Young, and Jun Chang. 2016. “In Hot Pursuit of the First Vaccine against Respiratory Syncytial Virus.” Yonsei Medical Journal. Yonsei University College of Medicine. doi:10.3349/ymj.2016.57.4.809.Nair, Harish, D. James Nokes, Bradford D. Gessner, Mukesh Dherani, Shabir A. Madhi, Rosalyn J. Singleton, Katherine L. O’Brien, et al. 2010. “Global Burden of Acute Lower Respiratory Infections Due to Respiratory Syncytial Virus in Young Children: A Systematic Review and Meta-Analysis.” The Lancet 375 (9725): 1545–55. doi:10.1016/S0140-6736(10)60206-1Walsh, Edward E. 2011. “Respiratory Syncytial Virus Infection in Adults.” Seminars in Respiratory and Critical Care Medicine 32 (4): 423–32. doi:10.1055/s-0031-1283282.Paramore, L. Clark, Vincent Ciuryla, Gabrielle Ciesla, and Larry Liu. 2004. “Economic Impact of Respiratory Syncytial Virus-Related Illness in the US: An Analysis of National Databases.” PharmacoEconomics 22 (5): 275–84. doi:10.2165/00019053-200422050-00001.Karime, L., Arango, O., & Durán, M. A. (2016). Virus sincitial respiratorio (vsr) en menores de 5 años, colombia, 2012 - 2016, 2012–2016. Retrieved from http://www.ins.gov.co/tramites-y-servicios/examenes-de-interés-en-salud-publica/Virologa/VSR en menores de 5 años.pdfInstituto Nacional de Salud. 2017. semana epidemiológica número 50. https://www.ins.gov.co/buscador-eventos/BoletinEpidemiologico/2017%20Bolet%C3%ADn%20epidemiol%C3%B3gico%20semana%2051.pdf?fbclid=IwAR0ycbHjXH1fDNI8jg156t0heaVcUf-RN6upV8LQubI1VT0GDFn6L7taXLUInstituto Nacional Salud. 2018. semana epidemiológica número 41. https://www.ins.gov.co/buscador-eventos/BoletinEpidemiologico/2018%20Bolet%C3%ADn%20epidemiol%C3%B3gico%20semana%2042.pdf?fbclid=IwAR27t1AfPANtFLqlqWn6caulmGE5n82cCyTGg__dvlqa4suT6W2RKlnuzYMBarbosa, Juliana, Beatriz Parra, Alarcón Liliana, Flor Inés Quiñones, Eduardo López, and Manuel Antonio Franco. 2017. “Prevalencia y Periodicidad Del Virus Sincitial Respiratorio En Colombia.” Rev. Acad. Colomb. Cienc. Ex. Fis. Nat. 41 (161): 435–46. doi:http://dx.doi.org/10.18257/raccefyn.511.Torres, Sandra Mónica Estupiñán, and Esperanza Trujillo Gama. 2004. “Complejo Mayor de Histocompatibilidad y Desarrollo de Vacunas.” NOVA. http://www.unicolmayor.edu.co/publicaciones/index.php/nova/article/view/24/47.Sánchez-Trincado, J. L., Gomez-Perosanz, M., & Reche, P. A. (2017). Fundamentals and Methods for T- and B-Cell Epitope Prediction. Journal of Immunology Research. Hindawi Limited. https://doi.org/10.1155/2017/2680160Arias-Murillo, Y., Castro-Jiménez, M., Ríos-Espinosa, M., López-Rivera, J., Echeverry-Coral, S., y Martínez-Nieto, O. (2011). Análisis de frecuencias alélicas, genotípicas y haplotípicas de HLA-A, HLA-B, HLA-DRB1 en la población colombiana. Colombia MéDica, 41 (4), 336-343. http://colombiamedica.univalle.edu.co/index.php/comedica/article/view/725/1186.Rodríguez Libia M, Giraldo Mabel C, García Natalia, Velásquez Laura, París Sara C, Álvarez Cristiam M et al . Frecuencias alélicas, genotípicas y haplotípicas HLA-A, HLA-B, HLA-DRB1 en donantes fallecidos, Medellín, Colombia. Biomédica [Internet]. 2007 Dec [cited 2018 Oct 27]; 27( 4 ): 537-547. Available from: http://www.scielo.org.co/scielo.php?script=sci_arttext&pid=S0120-41572007000400009&lng=en.Painter, Corrie A, and Lawrence J Stern. 2011. “Structural Insights Into HLA-DM Mediated MHC II Peptide Exchange.” Current Topics in Biochemical Research 13 (2): 39–55. doi:10.1016/j.biotechadv.2011.08.021.Secreted.Vargas L.E. et al. (2003) MHC allele-specific binding of a malaria peptide makes it become promiscuous on fitting a glycine residue into pocket 6. Biochemical and Biophysical Research Communications 307 148–156. doi:10.1016/S0006-291X(03)01129-XDay, Cheryl L, Nilufer P Seth, Michaela Lucas, Heiner Appel, Laurent Gauthier, Georg M Lauer, Gregory K Robbins, et al. 2003. “Ex Vivo Analysis of Human Memory CD4 T Cells Specific for Hepatitis C Virus Using MHC Class II Tetramers” 112 (6): 831–42. doi:10.1172/JCI200318509Yu, Yang, Dongdong Jin, Shizong Hu, Yan Zhang, Xiaojing Zheng, Jianhua Zheng, Mingfeng Liao, et al. 2015. “A Novel Tuberculosis Antigen Identified from Human Tuberculosis Granulomas.” Molecular & Cellular Proteomics 14 (4): 1093–1103. doi:10.1074/mcp.M114.045237.Yin, L., Maben, Z., Becerra, A., & Stern, L. J. (2015). Evaluating the role of HLA-DM in MHC II-peptide association reactions. Journal of Immunology (Baltimore, Md. : 1950), 195(2), 706–716. http://doi.org/10.4049/jimmunol.1403190Hurwitz, Julia L. 2011. “Respiratory Syncytial Virus Vaccine Development.” Expert Review of Vaccines. doi:10.1586/erv.11.120.Chanock, Robert M, Keith Jensen, and Robert H Parrott. 1969. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine1- 2- 89(4): 422–34.Graham, Barney S. 2016. “Vaccines against Respiratory Syncytial Virus: The Time Has Finally Come.” Vaccine 34 (30). Elsevier Ltd: 3535–41. doi:10.1016/j.vaccine.2016.04.083.Higgins, Deborah, Carrie Trujillo, and Cheryl Keech. 2016. “Advances in RSV Vaccine Research and Development - A Global Agenda.” Vaccine 34 (26). Elsevier Ltd: 2870–75. doi:10.1016/j.vaccine.2016.03.109.Rudraraju, R., Jones, B. G., Sealy, R., Surman, S. L., & Hurwitz, J. L. (2013). Respiratory syncytial virus: current progress in vaccine development. Viruses, 5(2), 577–94. https://doi.org/10.3390/v5020577J. Díez y V. Planelles.2011. Vacuna frente al virus respiratorio sincitial. An Pediatr Contin; 9(1):64-8. http://appswl.elsevier.es/watermark/ctl_servlet?_f=10&pident_articulo=80000599&pident_usuario=0&pcontactid=&pident_revista=51&ty=130&accion=L&origen=apccontinuada&web=www.apcontinuada.com&lan=es&fichero=v9n1a499pdf001.pdf&anuncioPdf=ERROR_publi_pdf&fbclid=IwAR0c_jnEkHdXA1XLCl83ySN4-10ZkQuVYBNHDKfIaio2nmtrgL90TjlBjq8Rodríguez Libia M, Giraldo Mabel C, García Natalia, Velásquez Laura, París Sara C, Álvarez Cristiam M et al . Frecuencias alélicas, genotípicas y haplotípicas HLA-A, HLA-B, HLA-DRB1 en donantes fallecidos, Medellín, Colombia. Biomédica [Internet]. 2007 Dec [cited 2018 Oct 27]; 27( 4 ): 537-547. Available from: http://www.scielo.org.co/scielo.php?script=sci_arttext&pid=S0120-41572007000400009&lng=enZhang, Lianming, Yiqing Chen, Hau San Wong, Shuigeng Zhou, Hiroshi Mamitsuka, and Shanfeng Zhu. 2012. “TepitopePan: Extending Tepitope for Peptide Binding Prediction Covering over 700 Hla-Dr Molecules.” PLoS ONE 7 (2). doi:10.1371/journal.pone.0030483Singh, Harpreet, and G. P.S. Raghava. 2002. “ProPred: Prediction of HLA-DR Binding Sites.” Bioinformatics 17 (12): 1236–37. doi:10.1093/bioinformatics/17.12.1236.Nielsen, Morten, Ole Lund, Soren Buus, and Claus Lundegaard. 2010. “MHC Class II Epitope Predictive Algorithms.” Immunology. doi:10.1111/j.1365-2567.2010.03268.x.Chaves, F. A., Lee, A. H., Nayak, J., Richards, K. A., & Sant, A. J. (2012). The utility and limitations of current web-available algorithms to predict peptides recognized by CD4 T cells in response to pathogen infection . Journal of Immunology (Baltimore, Md. : 1950), 188(9), 4235–4248. doi:10.4049/jimmunol.1103640.Marek Wieczorek, Esam T, Front Immunol. 2017; 8: 292. Published online 2017 Mar 17,Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355494/Secretaria distrital de salud.Curso basico de medicina transfusional.editorial maldonado SADeborah A. Lipski, Rémi Dewispelaere,MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis J Neuroinflammation. 2017; 14: 136Brown, J H, T S Jardetzky, J C Gorga, L J Stern, R G Urban, J L Strominger, and D C Wiley. 1993. “Three-Dimensional Structure of the Human Class II Histocompatibility Antigen HLA-DR1.” Nature 364 (6432): 33–39. doi:10.1038/364033a0William Sherwin, Lars, Bejder, Celine Frère, Michael Krützen, Janet Mann, Tracey Rogers. Fitness & major histocompatibility complex diversity of two bottlenose dolphin populations DOI: 10.13140/RG.2.1.1804.2480.Painter, Corrie A, and Lawrence J Stern. 2011. “Structural Insights Into HLA-DM Mediated MHC II Peptide Exchange.” Current Topics in Biochemical Research 13 (2): 39–55. doi:10.1016/j.biotechadv.2011.08.021.Secreted.Bian, Hongjin, John F. Reidhaar-Olson, and Juergen Hammer. 2003. “The Use of Bioinformatics for Identifying Class II-Restricted T-Cell Epitopes.” Methods 29 (3). Academic Press Inc.: 299–309. doi:10.1016/S1046-2023(02)00352-3.Mecanismos de procesamiento y presentación antigénica en autoinmunidad. Universidad Autónoma de Barcelona, Bellaterra Mayo 2017Braendstrup P, Mortensen BK, Justesen S, Østerby T, Rasmussen M, et al. (2014) Identification and HLA-Tetramer-Validation of Human CD4+ and CD8+ T Cell Responses against HCMV Proteins IE1 and IE2. PLoS ONE 9(4): doi:10.1371/journal.pone.0094892Blazekovic, F., Odukoya, D., Butler, S. N., Mauro, J. A., Ramsamooj, M., Puleo, E. Blanck, G. (2016). HLA-DR peptide occupancy can be regulated with a wide variety of small molecules. Human Vaccines and Immunotherapeutics, 12(3), 593–598. https://doi.org/10.1080/21645515.2015.1089370Steven G.E. Marsh, Peter Parham, Linda D. Barber. THE HLA. FactsBook Academic press.92101-4495. USA. Capítulo 7. Pag.41-73.Rammensee, H G. 1995. “Chemistry of Peptides Associated with MHC Class I and Class II Molecules.” Curr Opin Immunol 7 (1): 85–96. doi:0952-7915(95)80033-6.Matsumura, M, D H Fremont, P a Peterson, and I a Wilson. 1992. “Emerging Principles for the Recognition of Peptide Antigens by MHC Class I Molecules.” Science 257 (1991): 927–34.Scott Southwood, John Sidney, Akihiro Kondo, Marie-France del Guercio, Ettore Appella, Stephen Hoffman, Ralph T. Kubo, Robert W. Chesnut, Howard M Grey and Alessandro Sette. 1998, Several Common HLA-DR Types Share Largely Overlapping Peptide Binding Repertoires J Immunol. J Immunol 1998; 160:3363-3373; http://www.jimmunol.org/content/160/7/3363HLA-DRB1 major histocompatibility complex, class II, DR beta Gene ID: 3123.Dominguez Horta, María, y Noraylis Lorenzo Pérez, y Ariana Barbera Betancourt, y María Victoria Hernández Cuellar, y Ana María Torres Lima, y M. Nazabal, y H. Camacho, e Isabel María Hernández Cuellar, y Neisy Ortiz, y V. Morera, y Ramón Gabriel Padrón Palomares. 2006. "Caracterización de Moléculas HLA tipo II y evaluación de citocinas en pacientes cubanos con Artritis Reumatoide". Revista Cubana de Reumatología 8 (9-10): 43-51Júlia Kurkó Et al. 2013 Genetics of Rheumatoid Arthritis:A Comprehensive Review. Clin Rev Allergy Immunol; 45(2): 170–179. doi:10.1007/s12016-012-8346-7.Albert J. C Zaja,Michael P. Manns,2010,Advances in the Diagnosis, Pathogenesis, and Management of Autoimmune Hepatitis,GASTROENTEROLOGY ;139:58 –72,doi:10.1053/j.gastro.2010.04.053Kareem Sassi ,Jose M. Nieto ,Sammy Saab 2015,– Trasplante de Hepatitis Autoinmune, páginas 174-188, Capítulo 15Pos, W. et al. (2012) Crystal structure of the HLA-DM–HLA-DR1 complex defines mechanisms for rapid peptide selection. Cell 151, 1557–1568Yin, Liusong, and Lawrence J. Stern. 2013. “HLA-DM Focuses on Conformational Flexibility Around P1 Pocket to Catalyze Peptide Exchange.” Frontiers in Immunology 4. doi:10.3389/fimmu.2013.00336Liusong Yin, Zachary J. Maben, Aniuska Becerra and Lawrence J. Stern J Immunol July 15, 2015, 195 (2) 706-716; Evaluating the Role of HLA-DM in MHC Class II–Peptide Association Reactions DOI: https://doi.org/10.4049/jimmunol.1403190Gilca, Rodica, Gaston De Serres, Mireille Tremblay, Marie-Louise Vachon, Eric Leblanc, Michel G Bergeron, Pierre Dery, and Guy Boivin. 2006. “Distribution and Clinical Impact of Human Respiratory Syncytial Virus Genotypes in Hospitalized Children over 2 Winter Seasons.” The Journal of Infectious Diseases 193: 54–58. doi:10.1086/498526.Vandini, Silvia, Carlotta Biagi, and Marcello Lanari. 2017. “Respiratory Syncytial Virus: The Influence of Serotype and Genotype Variability on Clinical Course of Infection.” International Journal of Molecular Sciences. MDPI AG. doi:10.3390/ijms18081717.Johansson, Cecilia. 2016. “Respiratory Syncytial Virus Infection: An Innate Perspective.” F1000Research 5 (December): 2898. doi:10.12688/f1000research.9637.1.Melero, José A., Vicente Mas, and Jason S. McLellan. 2017. “Structural, Antigenic and Immunogenic Features of Respiratory Syncytial Virus Glycoproteins Relevant for Vaccine Development.” Vaccine 35 (3). Elsevier Ltd: 461–68. doi:10.1016/j.vaccine.2016.09.045.Griffiths C, Drews SJ, Marchant DJ. 2017. Respiratory syncytial virus: infection, detection, and new options for prevention and treatment. Clin Microbiol Rev 30:277–319. https://doi.org/10.1128/CMR.00010-16Emma Rey-Jurado and Alexis M. Kalergis.2017. Immunological Features of Respiratory Syncytial Virus-Caused Pneumonia—Implications for Vaccine Design.Int. J. Mol. Sci., 18, 556; doi:10.3390/ijms18030556Nicolás M. S. Gálvez, Jorge A. Soto, Alexis M. Kalergis,2017, New Insights Contributing to the Development of Effective Vaccines and Therapies to Reduce the Pathology Caused by hRSV. Int. J. Mol. Sci., 18, 1753; doi:10.3390/ijms18081753.Alexander Kotelkin, Igor M. Belyakov, Lijuan Yang, Jay A. Berzofsky, Peter L. Collins, and Alexander Bukreyev , 2006, The NS2 Protein of Human Respiratory Syncytial Virus Suppresses the Cytotoxic T-Cell Response as a Consequence of Suppressing the Type I Interferon Response. JOURNAL OF VIROLOGY,, p. 5958–5967 Vol. 80, doi:10.1128/JVI.00181-06.Claire P Straub, Wei-Har Lau, Faith M Preston, Madeleine J Headlam, Jeffery J Gorman, Peter L Collins and Kirsten M Spann,2011, Mutation of the elongin C binding domain of human respiratory syncytial virus non-structural protein 1 (NS1) results in degradation of NS1 and attenuation of the virus. Straub et al. Virology Journal, 8:252 https://doi.org/10.1186/1743-422X-8-252Hastie M et al. 2012 The Human Respiratory Syncytial Virus Nonstructural Protein 1 Regulates Type I and Type II Interferon Pathways.Molecular & Cellular Proteomics 11: 10.1074/ mcp.M111.015909, 108 –127Peter L. Collins. Rachel Fearns. Barney S. Graham,2013, espinoza Curr Top Microbiol Immunol. 2013; 372: 3–38. Doi:10.1007/978-3-642-38919-1_1.Céspedes P et al. .2014,Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells. PNAS,DOI:10.1073/pnas.1400760111.Ruchira Mitra, Pradyumna Baviskar, Rebecca R, 2012, Duncan-Decocq, Darshna Patel, and Antonius G. P. Oomens. The Human Respiratory Syncytial Virus Matrix Protein Is Required for Maturation of Viral Filaments. Journal of Virology p. 4432–4443. 2012.DOI:10.1128/JVI.06744-11Ghildyal, Reena, Adeline Ho, and David A. Jans. 2006. “Central Role of the Respiratory Syncytial Virus Matrix Protein in Infection.” FEMS Microbiology Reviews. doi:10.1111/j.1574-6976.2006.00025.x.Liang, Bo, Sonja Surman, Emerito Amaro-Carambot, Barbora Kabatova, Natalie Mackow, Matthias Lingemann, Lijuan Yang, et al. 2015. “Enhanced Neutralizing Antibody Response Induced by Respiratory Syncytial Virus Prefusion F Protein Expressed by a Vaccine Candidate.”. Journal of Virology 89 (18): 9499–9510. doi:10.1128/JVI.01373-15.Rossey, Iebe, Jason S. McLellan, Xavier Saelens, and Bert Schepens. 2017. “Clinical Potential of Prefusion RSV F-Specific Antibodies.” Trends in Microbiology. doi:10.1016/j.tim.2017.09.009.Gagliardi T, B, Criado M, F, Proença-Módena J, L, Saranzo A, M, Iwamoto M, A, de Paula F, E, Cardoso R, S, Delcaro L, S, Silva M, L, Câmara A, A, Arruda E: Syncytia Induction by Clinical Isolates of Human Respiratory Syncytial Virus A. Intervirology 2017;60:56-60. doi: 10.1159/000480014Carter, Stephen D., Kyle C. Dent, Elizabeth Atkins, Toshana L. Foster, Mark Verow, Petra Gorny, Mark Harris, et al. 2010. “Direct Visualization of the Small Hydrophobic Protein of Human Respiratory Syncytial Virus Reveals the Structural Basis for Membrane Permeability.” FEBS Letters 584 (13): 2786–90. doi:10.1016/j.febslet.2010.05.006.Fuentes, S., K. C. Tran, P. Luthra, M. N. Teng, and B. He. 2007. “Function of the Respiratory Syncytial Virus Small Hydrophobic Protein.” Journal of Virology 81 (15): 8361–66. doi:10.1128/JVI.02717-06.Schepens, Bert, Koen Sedeyn, Liesbeth Vande Ginste, Sarah De Baets, Michael Schotsaert, Kenny Roose, Lieselot Houspie, et al. 2014. “Protection and Mechanism of Action of a Novel Human Respiratory Syncytial Virus Vaccine Candidate Based on the Extracellular Domain of Small Hydrophobic Protein.” EMBO Mol Med 6: 1436–54. doi:10.15252/emmm.201404005.Schepens, Bert. 2015. “Small Hydrophobic Protein of Respiratory Syncytial Virus as a Novel Vaccine Antigen.” Immunotherapy 7: 203–6. doi:10.2217/imt.15.11.Melero, José A., Vicente Mas, and Jason S. McLellan. 2017. “Structural, Antigenic and Immunogenic Features of Respiratory Syncytial Virus Glycoproteins Relevant for Vaccine Development.” Vaccine 35 (3). Elsevier Ltd: 461–68. doi:10.1016/j.vaccine.2016.09.045.Boyoglu-Barnum S, Todd SO, Meng J, Barnum TR, Chirkova T, Haynes LM, Jadhao SJ, Tripp RA, Oomens AG, Moore ML, Anderson LJ. 2017. Mutating the CX3C motif in the G protein should make a live respiratory syncytial virus vaccine safer and more effective. J Virol 91:e02059-16. https:// doi.org/10.1128/JVI.02059-16.Chirkova, Tatiana, Songbai Lin, Antonius G P Oomens, Kelsey A Gaston, Seyhan Boyoglu-Barnum, Jia Meng, Christopher C Stobart, et al. 2015. “CX3CR1 Is an Important Surface Molecule for Respiratory Syncytial Virus Infection in Human Airway Epithelial Cells.” The Journal of General Virology 96 (9). Microbiology Society: 2543–56. doi:10.1099/vir.0.000218.Fix, J., Galloux, M., Blondot, M. L., & Eléouët, J. F. (2011). The insertion of fluorescent proteins in a variable region of respiratory syncytial virus L polymerase results in fluorescent and functional enzymes but with reduced activities. The open virology journal, 5, 103-8Castagné, Nathalie, Alexandra Barbier, Julie Bernard, Human Rezaei, Jean Claude Huet, Céline Henry, Bruno Da Costa, and Jean François Eléouët. 2004. “Biochemical Characterization of the Respiratory Syncytial Virus P-P and P-N Protein Complexes and Localization of the P Protein Oligomerization Domain.” Journal of General Virology 85 (6): 1643–53. doi:10.1099/vir.0.79830-0.Espinoza J, Bueno S, Riedel C, Kalergis A. 2014 Induction of protective effector immunity to prevent pathogenesis caused by the respiratory syncytial virus. Implications on therapy and vaccine designImmunology, 143, 1–12. doi:10.1111/imm.12313Rey-Jurado, E., & Kalergis, A. M. (2017). Immunological Features of Respiratory Syncytial Virus-Caused Pneumonia-Implications for Vaccine Design. International journal of molecular sciences, 18(3), 556. doi:10.3390/ijms18030556Mylene Corzo-López y Odalys Valdés-Ramírez.* El virus sincitial respiratorio humano: una panorámica, Revista CENIC Ciencias Biológicas, Vol. 44, No. 2, mayo-agosto, 2013.http://www.redalyc.org/pdf/1812/181227534005.pdfChartrand, C., Tremblay, N., Renaud, C., & Papenburg, J. (2015). Diagnostic Accuracy of Rapid Antigen Detection Tests for Respiratory Syncytial Virus Infection: Systematic Review and Meta-analysis. Journal of clinical microbiology, 53(12), 3738-49.Pilie, P., W. A. Werbel, J. Riddell, X. Shu, D. Schaubel, and K. S. Gregg. 2015. “Adult Patients with Respiratory Syncytial Virus Infection: Impact of Solid Organ and Hematopoietic Stem Cell Transplantation on Outcomes.” Transplant Infectious Disease 17 (4). Blackwell Publishing Inc.: 551–57. doi:10.1111/tid.12409.Paes, Bosco A., Ian Mitchell, Anna Banerji, Krista L. Lanctôt, and Joanne M. Langley. 2011. “A Decade of Respiratory Syncytial Virus Epidemiology and Prophylaxis: Translating Evidence into Everyday Clinical Practice.” Canadian Respiratory Journal. Hindawi Limited. doi:10.1155/2011/493056.Bont, Louis, Paul A. Checchia, Brigitte Fauroux, Josep Figueras-Aloy, Paolo Manzoni, Bosco Paes, Eric A.F. and Xavier Carbonell-Estrany. 2016. “Defining the Epidemiology and Burden of Severe Respiratory Syncytial Virus Infection Among Infants and Children in Western Countries.” Infectious Diseases and Therapy. Springer Healthcare. doi:10.1007/s40121-016-0123-0Robbie, G. J., Criste, R., Dall'acqua, W. F., Jensen, K., Patel, N. K., Losonsky, G. A., & Griffin, M. P. (2013). A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrobial agents and chemotherapy, 57(12), 6147-53.Graham BS,(2016) , Vaccines against respiratory syncytial virus: The time has finally come. Vaccine , http://dx.doi.org/10.1016/j.vaccine.2016.04.083J.A. Bastarache, T. Koyama, N.E Wickersham, and L.B. Ware, 2014 ;. Validation of a multiplex electrochemiluminescent immunoassay platform in human and mouse samples.J Immunol Methods, doi:10.1016/j.jim.2014.04.006.Rojas-Caraballo, J., López-Abán, J., Pérez Del Villar, L., Vizcaíno, C., Vicente, B., Fernández-Soto, P., Muro, A. (2014). In vitro and in vivo studies for assessing the immune response and protection-inducing ability conferred by Fasciola hepatica-derived synthetic peptides containing B- and T-cell epitopes. PLoS ONE, 9(8). https://doi.org/10.1371/journal.pone.0105323Creech AL, Ting YS,2018,The Role of Mass Spectrometry and Proteogenomics in the Advancement of HLA Epitope Prediction.Proteomics. doi: 10.1002/pmic.201700259.L.E VARGAS,2011, Influencia de HLA-DM en la estabilidad del complejo formado entre la molécula HLA-DR4 y un péptido de la proteína CS de P. falciparum. Universidad Nacional Facultad de Medicina, http://bdigital.unal.edu.co/8745/1/597342.2011.pdfYin, Liusong, Peter Trenh, Abigail Guce, Marek Wieczorek, Sascha Lange, Jana Sticht, Wei Jiang, et al. 2014. “Susceptibility to HLA-DM Protein Is Determined by a Dynamic Conformation of Major Histocompatibility Complex Class II Molecule Bound with Peptide.” Journal of Biological Chemistry 289 (34). American Society for Biochemistry and Molecular Biology Inc.: 23449–64. doi:10.1074/jbc.M114.585539Yin, L., J. M. Calvo-Calle, O. Dominguez-Amorocho, and L. J. Stern. 2012. “HLA-DM Constrains Epitope Selection in the Human CD4 T Cell Response to Vaccinia Virus by Favoring the Presentation of Peptides with Longer HLA-DM-Mediated Half-Lives.” The Journal of Immunology 189 (8): 3983–94. doi:10.4049/jimmunol.1200626.Hall, Frances C., Joshua D. Rabinowitz, Robert Busch, Kevin C. Visconti, Michael Belmares, Namrata S. Patil, Andrew P. Cope, et al. 2002. “Relationship between Kinetic Stability and Immunogenicity of HLA- DR4/Peptide Complexes.” European Journal of Immunology 32 (3): 662–70. doi:10.1002/1521-4141(200203)32:3<662::AID-IMMU662>3.0.CO;2-5.Lin, Hong Huang, Guang Lan Zhang, Songsak Tongchusak, Ellis L. Reinherz, and Vladimir Brusic. 2008. “Evaluation of MHC-II Peptide Binding Prediction Servers: Applications for Vaccine Research.” In BMC Bioinformatics. Vol. 9. doi:10.1186/1471-2105-9-S1-S22Achal Pashine, Robert Busch, 2003, Interaction of HLA-DR with an Acidic Face of HLA-DM Disrupts Sequence-Dependent Interactions with Peptides. Immunity, Vol. 19, 183–192,DOI:https://doi.org/10.1016/S1074-7613(03)00200-0.Viviana Marin-Esteban, Kirsten Falk,Chemical ,2004,Analogues of HLA-DM Can Induce a Peptide-receptive State in HLA-DR Molecules. JBC Papers in Press, DOI 10.1074/jbc.M407598200.Alvarado A, Tenorio G.V R, Aguilar S,A, Sandoval T,AH.2006.Promesas y limitaciones de las vacunas antigénicas. Revista Mexicana de ciencias Farmacéuticas. [Internet]:37(2):26-37. http://www.redalyc.org/pdf/579/57937205.pdfEl Virus Sincitial RespiratorioPatologías NeuromuscularesBronquiolitisParamyxoviridaePresentación de antígenosSelección de EpítopesComplejo MHC II/PéptidoSusceptibilidad HLA-DMAlgoritmos de unión a moléculas MHC clase IIMoléculas HLA-DR1 y DR4ORIGINALCartas derechos de autor.pdfCartas derechos de autor.pdfapplication/pdf386848https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/1/Cartas%20derechos%20de%20autor.pdf7f85c42e8331618a76f9c7fa2491f459MD51metadata only accessProyecto de grado..pdfProyecto de grado..pdfapplication/pdf1204972https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/2/Proyecto%20de%20grado..pdf67ea10eb9569e0133c83c4baec9ddc65MD52open accessProyecto de Grado.pdfProyecto de Grado.pdfapplication/pdf2280952https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/3/Proyecto%20de%20Grado.pdf6f81e2856e715de46bc00e1cb62aabe4MD53open accessLICENSElicense.txtlicense.txttext/plain; charset=utf-814828https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/4/license.txt2f9959eaf5b71fae44bbf9ec84150c7aMD54open accessTEXTCartas derechos de autor.pdf.txtCartas derechos de autor.pdf.txtExtracted texttext/plain15https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/5/Cartas%20derechos%20de%20autor.pdf.txtd3055369a061017d1d1bd3375129a6dfMD55metadata only accessProyecto de grado..pdf.txtProyecto de grado..pdf.txtExtracted texttext/plain146215https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/7/Proyecto%20de%20grado..pdf.txt6d720b4218f8a01e3dcb6ec334a891e7MD57open accessProyecto de Grado.pdf.txtProyecto de Grado.pdf.txtExtracted texttext/plain8122https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/9/Proyecto%20de%20Grado.pdf.txtb2068747021ce9804b5a182532c91482MD59open accessTHUMBNAILCartas derechos de autor.pdf.jpgCartas derechos de autor.pdf.jpgGenerated Thumbnailimage/jpeg7803https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/6/Cartas%20derechos%20de%20autor.pdf.jpg2024383a0ea8e4f51d1962b0a5a3b24aMD56metadata only accessProyecto de grado..pdf.jpgProyecto de grado..pdf.jpgGenerated Thumbnailimage/jpeg6702https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/8/Proyecto%20de%20grado..pdf.jpg73861401e49b8680c021515d0fc12c1bMD58open accessProyecto de Grado.pdf.jpgProyecto de Grado.pdf.jpgGenerated Thumbnailimage/jpeg7410https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3569/10/Proyecto%20de%20Grado.pdf.jpg973a00fad391c3a95ece74134131e8c9MD510open accessunicolmayor/3569oai:repositorio.unicolmayor.edu.co:unicolmayor/35692021-10-28 03:00:41.594An error occurred on the license name.|||https://creativecommons.org/licenses/by-nc-sa/4.0/metadata only accessBiblioteca Digital Unicolmayorrepositorio@unicolmayor.edu.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