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RESUMEN DE LOS AVANCES EN INVESTIGACIÓN BÁSICA Pepe Alcami Unidad de Inmunopatologia del SIDA Instituto de SaIud Carlos III I.P.

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Presentación del tema: "RESUMEN DE LOS AVANCES EN INVESTIGACIÓN BÁSICA Pepe Alcami Unidad de Inmunopatologia del SIDA Instituto de SaIud Carlos III I.P."— Transcripción de la presentación:

1 RESUMEN DE LOS AVANCES EN INVESTIGACIÓN BÁSICA Pepe Alcami Unidad de Inmunopatologia del SIDA Instituto de SaIud Carlos III I.P.

2 CD4 1.Virologia Factores celulares Nuevos mecanismos de entrada Latencia Reactivación 2.Inmunologia Celulas T reguladoras Vacunas 3.Casos especiales I.P.

3 CICLO BIOLOGICO DEL VIH

4 Membrana celular Barrera de actina APOBEC Niveles de nucleótidos Membrana nuclear Transcripcion Nucleosoma EMERIN LEDGF

5 FACTORES QUE FAVORECEN LA INTEGRACIÓN EMERIN, LEDGF The LEM domain proteins emerin and LAP2alpha are dispensable for human immunodeficiency virus type 1 and murine leukemia virus infections. Mulky A, Cohen TV, Kozlov SV, Korbei B, Foisner R, Stewart CL, KewalRamani VN. J Virol Jun;82(12): Epub 2008 Apr 9. Wild-type levels of human immunodeficiency virus type 1 infectivity in the absence of cellular emerin protein. Shun MC, Daigle JE, Vandegraaff N, Engelman A. J Virol Jan;81(1): Epub 2006 Oct 11. Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site Virology: HIV goes nuclear. Li M, Craigie R. Nature Jun 1;441(7093): No abstract available. The inner-nuclear-envelope protein emerin regulates HIV-1 infectivity. Jacque JM, Stevenson M. Nature Jun 1;441(7093): Epub 2006 May 7.

6 Affinities between the binding partners of the HIV-1 integrase dimer/lens epithelium derived growth factor (in dimer/LEDGF) complex. Tsiang M, Jones GS, Hung M, Mukund S, Han B, Liu X, Babaoglu K, Lansdon E, Chen X, Todd J, Cai T, Pagratis N, Sakowicz R, Geleziunas R. J Biol Chem Sep 28. [Epub ahead of print] Barrier-to-autointegration factor proteome reveals chromatin-regulatory partners. Montes de Oca R, Shoemaker CJ, Gucek M, Cole RN, Wilson KL. PLoS One Sep 16;4(9):e7050. FACTORES QUE FAVORECEN LA INTEGRACIÓN EMERIN, LEDGF

7 Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Neil SJ, Zang T, Bieniasz PD. Nature Jan 24;451(7177): Epub 2008 Jan 16. PMID: [PubMed - indexed for MEDLINE] Related Articles

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10 HIV-1 accessory protein Vpu internalizes cell-surface BST-2/tetherin through transmembrane interactions leading to lysosomes. Iwabu Y, Fujita H, Kinomoto M, Kaneko K, Ishizaka Y, Tanaka Y, Sata T, Tokunaga K. J Biol Chem Oct 16. [Epub ahead of print] 2: Effect of Calcium Modulating Cyclophilin Ligand (CAML) on HIV-1 particle release and Tetherin cell-surface expression. Bego MG, Dubé M, Mercier J, Cohen EA. J Virol Sep 30. [Epub ahead of print] PMID: [PubMed - as supplied by publisher] Related Articles 3: Antagonism and intracellular sequestration of human tetherin by the HIV-2 envelope glycoprotein. Le Tortorec A, Neil SJ. J Virol Sep 9. [Epub ahead of print] PMID: [PubMed - as supplied by publisher] Related Articles 4: The formation of cysteine-linked dimers of BST-2/tetherin is important for inhibition of HIV-1 virus release but not for sensitivity to Vpu. Andrew AJ, Miyagi E, Kao S, Strebel K. Retrovirology Sep 8;6:80. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 5: HIV-1 Vpu neutralizes the antiviral factor Tetherin/BST-2 by binding it and directing its beta-TrCP2-dependent degradation. Mangeat B, Gers-Huber G, Lehmann M, Zufferey M, Luban J, Piguet V. PLoS Pathog Sep;5(9):e Epub 2009 Sep 4. PMID: [PubMed - in process] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 6: Evolutionary Trajectories of Primate Genes Involved in HIV Pathogenesis. Ortiz M, Guex N, Patin E, Martin O, Xenarios I, Ciuffi A, Quintana-Murci L, Telenti A. Mol Biol Evol Sep 2. [Epub ahead of print] PMID: [PubMed - as supplied by publisher] Related Articles 7: SIMIAN IMMUNODEFICIENCY VIRUS FROM AFRICAN GREEN MONKEYS (SIVAGM) DOES NOT ANTAGONIZE ENDOGENOUS LEVELS OF AFRICAN GREEN MONKEY TETHERIN/BST-2. Lim E, Emerman M. J Virol Sep 2. [Epub ahead of print] PMID: [PubMed - as supplied by publisher] Related Articles 8: Molecular mechanism of BST2/tetherin downregulation by K5/MIR2 of Kaposi's sarcoma-associated herpesvirus. Mansouri M, Viswanathan K, Douglas JL, Hines J, Gustin J, Moses AV, Früh K. J Virol Oct;83(19): Epub 2009 Jul 15. PMID: [PubMed - indexed for MEDLINE] Related Articles 9: A New World primate deficient in tetherin-mediated restriction of human immunodeficiency virus type 1. Wong SK, Connole M, Sullivan JS, Choe H, Carville A, Farzan M. J Virol Sep;83(17): Epub 2009 Jun 24. PMID: [PubMed - indexed for MEDLINE] Related Articles 10: Vpu directs the degradation of the human immunodeficiency virus restriction factor BST-2/Tetherin via a {beta}TrCP-dependent mechanism. Douglas JL, Viswanathan K, McCarroll MN, Gustin JK, Früh K, Moses AV. J Virol Aug;83(16): Epub 2009 Jun 10. PMID: [PubMed - indexed for MEDLINE] Related Articles 11: Nef proteins from simian immunodeficiency viruses are tetherin antagonists. Zhang F, Wilson SJ, Landford WC, Virgen B, Gregory D, Johnson MC, Munch J, Kirchhoff F, Bieniasz PD, Hatziioannou T. Cell Host Microbe Jul 23;6(1): Epub 2009 Jun 4. PMID: [PubMed - indexed for MEDLINE] Related Articles 12: Comparative study on the effect of human BST-2/Tetherin on HIV-1 release in cells of various species. Sato K, Yamamoto SP, Misawa N, Yoshida T, Miyazawa T, Koyanagi Y. Retrovirology Jun 2;6:53. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 13: Vpu antagonizes BST-2-mediated restriction of HIV-1 release via beta-TrCP and endo-lysosomal trafficking. Mitchell RS, Katsura C, Skasko MA, Fitzpatrick K, Lau D, Ruiz A, Stephens EB, Margottin-Goguet F, Benarous R, Guatelli JC. PLoS Pathog May;5(5):e Epub 2009 May 29. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 14: The transmembrane domain of BST-2 determines its sensitivity to down-modulation by human immunodeficiency virus type 1 Vpu. Rong L, Zhang J, Lu J, Pan Q, Lorgeoux RP, Aloysius C, Guo F, Liu SL, Wainberg MA, Liang C. J Virol Aug;83(15): Epub 2009 May 27. PMID: [PubMed - indexed for MEDLINE] Related Articles 15: Mutation of a single residue renders human tetherin resistant to HIV-1 Vpu-mediated depletion. Gupta RK, Hué S, Schaller T, Verschoor E, Pillay D, Towers GJ. PLoS Pathog May;5(5):e Epub 2009 May 22. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 16: Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2. Jia B, Serra-Moreno R, Neidermyer W, Rahmberg A, Mackey J, Fofana IB, Johnson WE, Westmoreland S, Evans DT. PLoS Pathog May;5(5):e Epub 2009 May 15. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 17: HIV-1 antagonism of CD317 is species specific and involves Vpu-mediated proteasomal degradation of the restriction factor. Goffinet C, Allespach I, Homann S, Tervo HM, Habermann A, Rupp D, Oberbremer L, Kern C, Tibroni N, Welsch S, Krijnse- Locker J, Banting G, Kräusslich HG, Fackler OT, Keppler OT. Cell Host Microbe Mar 19;5(3): PMID: [PubMed - indexed for MEDLINE] Related Articles 18: Suppression of Tetherin-restricting activity upon human immunodeficiency virus type 1 particle release correlates with localization of Vpu in the trans-Golgi network. Dubé M, Roy BB, Guiot-Guillain P, Mercier J, Binette J, Leung G, Cohen EA. J Virol May;83(9): Epub 2009 Feb 25. PMID: [PubMed - indexed for MEDLINE] Related Articles 19: Species-specific activity of HIV-1 Vpu and positive selection of tetherin transmembrane domain variants. McNatt MW, Zang T, Hatziioannou T, Bartlett M, Fofana IB, Johnson WE, Neil SJ, Bieniasz PD. PLoS Pathog Feb;5(2):e Epub 2009 Feb 13. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 20: Vpu enhances HIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletion. Miyagi E, Andrew AJ, Kao S, Strebel K. Proc Natl Acad Sci U S A Feb 24;106(8): Epub 2009 Feb 5. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site HIV-1 accessory protein Vpu internalizes cell-surface BST-2/tetherin through transmembrane interactions leading to lysosomes. Iwabu Y, Fujita H, Kinomoto M, Kaneko K, Ishizaka Y, Tanaka Y, Sata T, Tokunaga K. J Biol Chem Oct 16. [Epub ahead of print] PMID: [PubMed - as supplied by publisher] Related ArticlesRelated Articles Free article at journal siteFree article at journal site 2: Effect of Calcium Modulating Cyclophilin Ligand (CAML) on HIV-1 particle release and Tetherin cell-surface expression. Bego MG, Dubé M, Mercier J, Cohen EA. J Virol Sep 30. [Epub ahead of print] PMID: [PubMed - as supplied by publisher] Related Articles 3: Antagonism and intracellular sequestration of human tetherin by the HIV-2 envelope glycoprotein. Le Tortorec A, Neil SJ. J Virol Sep 9. [Epub ahead of print] PMID: [PubMed - as supplied by publisher] Related Articles 4: The formation of cysteine-linked dimers of BST-2/tetherin is important for inhibition of HIV-1 virus release but not for sensitivity to Vpu. Andrew AJ, Miyagi E, Kao S, Strebel K. Retrovirology Sep 8;6:80. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 5: HIV-1 Vpu neutralizes the antiviral factor Tetherin/BST-2 by binding it and directing its beta-TrCP2-dependent degradation. Mangeat B, Gers-Huber G, Lehmann M, Zufferey M, Luban J, Piguet V. PLoS Pathog Sep;5(9):e Epub 2009 Sep 4. PMID: [PubMed - in process] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 6: Evolutionary Trajectories of Primate Genes Involved in HIV Pathogenesis. Ortiz M, Guex N, Patin E, Martin O, Xenarios I, Ciuffi A, Quintana-Murci L, Telenti A. Mol Biol Evol Sep 2. [Epub ahead of print] PMID: [PubMed - as supplied by publisher] Related Articles 7: SIMIAN IMMUNODEFICIENCY VIRUS FROM AFRICAN GREEN MONKEYS (SIVAGM) DOES NOT ANTAGONIZE ENDOGENOUS LEVELS OF AFRICAN GREEN MONKEY TETHERIN/BST-2. Lim E, Emerman M. J Virol Sep 2. [Epub ahead of print] PMID: [PubMed - as supplied by publisher] Related Articles 8: Molecular mechanism of BST2/tetherin downregulation by K5/MIR2 of Kaposi's sarcoma-associated herpesvirus. Mansouri M, Viswanathan K, Douglas JL, Hines J, Gustin J, Moses AV, Früh K. J Virol Oct;83(19): Epub 2009 Jul 15. PMID: [PubMed - indexed for MEDLINE] Related Articles 9: A New World primate deficient in tetherin-mediated restriction of human immunodeficiency virus type 1. Wong SK, Connole M, Sullivan JS, Choe H, Carville A, Farzan M. J Virol Sep;83(17): Epub 2009 Jun 24. PMID: [PubMed - indexed for MEDLINE] Related Articles 10: Vpu directs the degradation of the human immunodeficiency virus restriction factor BST-2/Tetherin via a {beta}TrCP-dependent mechanism. Douglas JL, Viswanathan K, McCarroll MN, Gustin JK, Früh K, Moses AV. J Virol Aug;83(16): Epub 2009 Jun 10. PMID: [PubMed - indexed for MEDLINE] Related Articles 11: Nef proteins from simian immunodeficiency viruses are tetherin antagonists. Zhang F, Wilson SJ, Landford WC, Virgen B, Gregory D, Johnson MC, Munch J, Kirchhoff F, Bieniasz PD, Hatziioannou T. Cell Host Microbe Jul 23;6(1): Epub 2009 Jun 4. PMID: [PubMed - indexed for MEDLINE] Related Articles 12: Comparative study on the effect of human BST-2/Tetherin on HIV-1 release in cells of various species. Sato K, Yamamoto SP, Misawa N, Yoshida T, Miyazawa T, Koyanagi Y. Retrovirology Jun 2;6:53. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 13: Vpu antagonizes BST-2-mediated restriction of HIV-1 release via beta-TrCP and endo-lysosomal trafficking. Mitchell RS, Katsura C, Skasko MA, Fitzpatrick K, Lau D, Ruiz A, Stephens EB, Margottin-Goguet F, Benarous R, Guatelli JC. PLoS Pathog May;5(5):e Epub 2009 May 29. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 14: The transmembrane domain of BST-2 determines its sensitivity to down- modulation by human immunodeficiency virus type 1 Vpu. Rong L, Zhang J, Lu J, Pan Q, Lorgeoux RP, Aloysius C, Guo F, Liu SL, Wainberg MA, Liang C. J Virol Aug;83(15): Epub 2009 May 27. PMID: [PubMed - indexed for MEDLINE] Related Articles 15: Mutation of a single residue renders human tetherin resistant to HIV-1 Vpu- mediated depletion. Gupta RK, Hué S, Schaller T, Verschoor E, Pillay D, Towers GJ. PLoS Pathog May;5(5):e Epub 2009 May 22. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 16: Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2. Jia B, Serra-Moreno R, Neidermyer W, Rahmberg A, Mackey J, Fofana IB, Johnson WE, Westmoreland S, Evans DT. PLoS Pathog May;5(5):e Epub 2009 May 15. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 17: HIV-1 antagonism of CD317 is species specific and involves Vpu-mediated proteasomal degradation of the restriction factor. Goffinet C, Allespach I, Homann S, Tervo HM, Habermann A, Rupp D, Oberbremer L, Kern C, Tibroni N, Welsch S, Krijnse-Locker J, Banting G, Kräusslich HG, Fackler OT, Keppler OT. Cell Host Microbe Mar 19;5(3): PMID: [PubMed - indexed for MEDLINE] Related Articles 18: Suppression of Tetherin-restricting activity upon human immunodeficiency virus type 1 particle release correlates with localization of Vpu in the trans- Golgi network. Dubé M, Roy BB, Guiot-Guillain P, Mercier J, Binette J, Leung G, Cohen EA. J Virol May;83(9): Epub 2009 Feb 25. PMID: [PubMed - indexed for MEDLINE] Related Articles 19: Species-specific activity of HIV-1 Vpu and positive selection of tetherin transmembrane domain variants. McNatt MW, Zang T, Hatziioannou T, Bartlett M, Fofana IB, Johnson WE, Neil SJ, Bieniasz PD. PLoS Pathog Feb;5(2):e Epub 2009 Feb 13. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site 20: Vpu enhances HIV-1 virus release in the absence of Bst-2 cell surface down- modulation and intracellular depletion. Miyagi E, Andrew AJ, Kao S, Strebel K. Proc Natl Acad Sci U S A Feb 24;106(8): Epub 2009 Feb 5. PMID: [PubMed - indexed for MEDLINE] Related ArticlesRelated Articles Free article in PMC | at journal siteFree article in PMC | at journal site

11 SUCEPTIBILIDAD A LA INFECCIÓN Y REPLICACIÓN VIRAL Linfocito en reposo Linfocito activado Resistencia a la infección Susceptible a infección LatenciaReplicación masiva

12 Apobec3 encodes Rfv3, a gene influencing neutralizing antibody control of retrovirus infection. Santiago ML, Montano M, Benitez R, Messer RJ, Yonemoto W, Chesebro B, Hasenkrug KJ, Greene WC. Science Sep 5;321(5894): Endogenous factors enhance HIV infection of tissue naive CD4 T cells by stimulating high molecular mass APOBEC3G complex formation. Kreisberg JF, Yonemoto W, Greene WC. J Exp Med Apr 17;203(4): Epub 2006 Apr 10

13 CD4 1.Virologia Factores celulares Nuevos mecanismos de entrada Latencia Reactivación 2.Inmunologia Celulas T reguladoras Vacunas 3.Casos especiales I.P.

14 Exposición del dominio de fusión 2 trímeros env E ) Formación estructura 6-hélices. Fusión de las membranas D) Liberación del dominio de fusión y anclaje en las membranas viral y celular. A) Envuelta VIH CD4 Exposición del dominio de unión al correceptor C) Interacción con los coreceptores B) Interacción con CD4 y cambio conformacional de la gp120 gp120 gp41 HR1 HR2 correceptor Dinámica del proceso de fusión

15 Pero las cosas no son fáciles…

16

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18 Trogocytosis… Active process of cellular communication, different from proteolitic cleavage or exosome transfer. Intercellular exchange of antigens/membranes.

19 CD4 1.Virologia Factores celulares Nuevos mecanismos de entrada Latencia Reactivación 2.Inmunologia Celulas T reguladoras Vacunas 3.Casos especiales I.P.

20 Box 2. Mechanisms for generation of HIV-1 latency. Transcriptional interference due to the site and orientation of the provirus within the cell chromosome. Epigenetic silencing by posttranscriptional modifications of the histone tails that form the nucleosome core and modulate the chromatin structure (e.g. hypoacetylation, trimethylation). Absence of nuclear host transcription activators for HIV-1 expression (e.g. NF- B, NF-AT, Sp1). Presence of cellular transcriptional repressors (e.g. YY1, LSF, CBF-1, APOBEC3G, I B, COMMD1). Inefficient elongation of HIV-1 transcripts due to the absence of the viral protein Tat and Tat-associated viral factors. Unproductive control of viral RNA splicing due to the absence of the viral protein Rev. Innate host antiviral processes (siRNA, miRNA).

21 RNA DE INTERFERENCIA E INFECCION VIH

22 Latently infected lymphocytes VIRAL REPLICATION IN NAIVE PATIENTS Viral propagation Infection of new targets Lymphocyte destruction ? Replenishment of reservoirs Persistent replication Low level ongoing replication Reactivation IM-SUP HAART INT POTENTIAL SOURCES OF RESIDUAL VIREMIA IN HAART Activated lymphocytes IM-SUP Homeostatic cell division Persistent replication Robust replication Other infected cell types (?) New cycles of infection REACTHAART + HIGH-LEVEL VIREMIA RESIDUAL VIREMIA (?)

23 Analysis of human immunodeficiency virus type 1 viremia and provirus in resting CD4+ T cells reveals a novel source of residual viremia in patients on antiretroviral therapy. Brennan TP, Woods JO, Sedaghat AR, Siliciano JD, Siliciano RF, Wilke. J Virol Sep;83(17): Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Dinoso JB, Kim SY, Wiegand AM, Palmer SE, Gange SJ, Cranmer L, O'Shea A, Callender M, Spivak A, Brennan T, Kearney MF, Proschan MA, Mican JM, Rehm CA, Coffin JM, Mellors JW, Siliciano RF, Maldarelli F. Proc Natl Acad Sci U S A Jun 9;106(23): Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs. Coiras M, López-Huertas MR, Pérez-Olmeda M, Alcamí J. Nat Rev Microbiol Nov;7(11): LATENCIA Y REACTIVACION HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, Boucher G, Boulassel MR, Ghattas G, Brenchley JM, Schacker TW, Hill BJ, Douek DC, Routy JP, Haddad EK, Sékaly RP. Nat Med Aug;15(8): Epub 2009 Jun 21

24 CD4 1.Virologia Factores celulares Nuevos mecanismos de entrada Latencia Reactivación 2.Inmunologia Celulas T reguladoras Vacunas 3.Casos especiales I.P.

25 Viral envelope gp41 2G12 2F5 CD4bs gp120 b12 4E10/Z13 (Burton D. Human neutralizing antibodies and a vaccine for HIV-1. XIV International AIDS Conference [Abstract nº201]) Tipos de anticuerpos neutralizantes. Dominios de neutralización dominio interacción coreceptores dominio de fusión dominio interacción CD4 dominios variables

26 Patient 1: Neutralizing HIV Antibody Titers of Sequential Plasma Specimens against Autologous Virus Dates Virus (months) /2/ /29/ /29/ /31/ /30/ /22/ /14/ /30/ /11/ Control NL JRCSF Plasma (months) ( D.Richman Rapid evolution of the neutralizing antibody response following primary HIV infection. XIV International AIDS Conference. [Abstract nº1051])

27 EL GRAN DESAFIO: OBTENER ANTICUERPOS NEUTRALIZANTES Karlsson et al. Nat.Rev.Microbiol 2008

28 Antibody induction Reverse Vaccinology (Burton D. Human neutralizing antibodies and a vaccine for HIV-1. XIV International AIDS Conference [Abstract nº201])

29 ESTRATEGIAS DE MODIFICACIÓN DE LA ENVUELTA PARA INCREMENTAR SU INMUNOGENICIDAD o Inmunizar con envueltas triméricas o Estabilizar la envuelta mediante la unión a otras proteínas: IgG o Direccionar la envuelta fusionandola a otras proteínas: CD40 o Acoplarla a nanopartículas que la dirijan a las células dendríticas. o Generar envueltas truncadas que expongan los dominios de interacción con los receptores

30 ANTICUERPOS NEUTRALIZANTES ¿QUE TIENEN QUE NO TENGAN LOS OTROS? 4E10 Anticuerpo frente a gp41: estructura de bucle 2F5 Anticuerpo frente a gp41: estructura helicoidal b12 Anticuerpo frente al dominio de interacción con CD D Anticuerpo frente al dominio V3-lamina beta que interacciona con el receptor CCR5 17b Anticuerpo frente a un epitopo inducido tras el desplegamiento de gp120 por CD4 (CD4i) 2g12 Anticuerpo dirigido frente a estructuras glicano

31 (Burton D. Human neutralizing antibodies and a vaccine for HIV-1. XIV International AIDS Conference [Abstract nº201]) Structure of b12 neutralising antibody

32 ESTRATEGIAS DE DISEÑO DE INMUNÓGENOS 4E10, 2F5 anticuerpos frente a gp41 En fase de definición a nivel atómico Acoplamiento en lisosomas b12 Anticuerpo frente al dominio de interacción con CD4 Investigación sobre anticuerpos de camélidos ¿Posible inducirlos en humanos? Base genética D Anticuerpo frente al dominio V3-lamina beta que interacciona con el receptor CCR5 Potenciar su inmunogenicidad 17b Anticuerpo frente a un epitopo inducido tras el desplegamiento de gp120 por CD4 (CD4i) Desplegar la gp120 con anticuerpos bivalentes, CD4 soluble o acoplamiento del epitopo a otras estructuras

33 ESTRATEGIAS DE DISEÑO DE INMUNÓGENOS 2G12 Anticuerpo dirigido frente a estructuras glicano Se une con igual afinidad a Candida Albicans que a gp120 Identificación de dichos epítopos/anticuerpos en el Sindrome de Guillain-Barré Sistemas de produccion de mann-8 en Sacharomices Cerevisiae: inmunización en conejos induce anticuerpos neutralizantes similares a 2G12 que neutralizan el VIH Modificacion para aumentar su inmunogenicidad. Acoplamiento a nanoparticulas para aumentar la estabilidad del epítopo.

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35 ¿Qué podemos esperar de una vacuna frente al VIH? Protección completa de la infección Protección parcial Infección con cargas virales a un nivel más bajo Los riesgos de la reducción de objetivos UTILIZAR VACUNAS NO PROTECTORAS UTILIZAR VACUNAS CON BAJO GRADO DE PROTECCIÓN MAS POLEMICAS: EL PROBLEMA DE LA REDUCCION DE OBJETIVOS

36 Walker B. NEJM Pilcher CD. J Clin Invest Walker B. NEJM Pilcher CD. J Clin Invest MicrobicidasMicrobicidas Fracaso ensayos fase II y III Nueva generacion demicrobicidas Nuevos mecanismos de liberacion Microbicida oral Fracaso ensayos fase II y III Nueva generacion demicrobicidas Nuevos mecanismos de liberacion Microbicida oral

37 SUJETO DE BERLIN (NUEVO)

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