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RESUMEN DE LOS AVANCES EN INVESTIGACIÓN BÁSICA

I.P. RESUMEN DE LOS AVANCES EN INVESTIGACIÓN BÁSICA. Pepe Alcami Unidad de Inmunopatologia del SIDA Instituto de SaIud Carlos III. I.P. CD4. Virologia Factores celulares Nuevos mecanismos de entrada Latencia Reactivación Inmunologia Celulas T reguladoras Vacunas Casos especiales.

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RESUMEN DE LOS AVANCES EN INVESTIGACIÓN BÁSICA

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

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

  3. Maturation CD4 gp120/gp41 Reverse transcriptase Microtubular network CXCR4/CCR5 Reverse transcription complex (RTC) Viral RNA Budding Proviral DNA synthesis Assembly Full- and short-length dscDNA Pre-integration latency Matrix protein Vpr Pre-integration complex (PIC) Actin filaments Nuclear pore complex (NPC) Integrase Structural proteins Genomic RNA Linear dscDNA Nuclear import Nuclear membrane Pre-integration latency Ribosomal traslation Post-integration latency Regulatory proteins Provirus NF-B, Sp1, NF-AT Circular non-integrated DNA Transcription Integration Tat Cellular DNA Efficient elongation Rev Multiple spliced mRNA Unspliced mRNA CICLO BIOLOGICO DEL VIH

  4. Maturation CD4 gp120/gp41 Reverse transcriptase Microtubular network CXCR4/CCR5 Reverse transcription complex (RTC) Viral RNA Budding Proviral DNA synthesis Assembly Full- and short-length dscDNA Pre-integration latency Matrix protein Vpr Pre-integration complex (PIC) Actin filaments Nuclear pore complex (NPC) Integrase Structural proteins Genomic RNA Linear dscDNA Nuclear import Nuclear membrane Pre-integration latency Ribosomal traslation Post-integration latency Regulatory proteins Provirus NF-B, Sp1, NF-AT Circular non-integrated DNA Transcription Integration Tat Cellular DNA Efficient elongation Rev Multiple spliced mRNA Unspliced mRNA CICLO BIOLOGICO DEL VIH Membrana celular Barrera de actina APOBEC Niveles de nucleótidos Membrana nuclear EMERIN LEDGF Transcripcion Nucleosoma

  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. 2008 Jun;82(12):5860-8. 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. 2007 Jan;81(1):166-72. Epub 2006 Oct 11. Related ArticlesFree article in PMC | at journal site Virology: HIV goes nuclear. Li M, Craigie R. Nature. 2006 Jun 1;441(7093):581-2. No abstract available. The inner-nuclear-envelope protein emerin regulates HIV-1 infectivity. Jacque JM, Stevenson M. Nature. 2006 Jun 1;441(7093):641-5. Epub 2006 May 7.

  6. FACTORES QUE FAVORECEN LA INTEGRACIÓN EMERIN, LEDGF 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. 2009 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. 2009 Sep 16;4(9):e7050.

  7. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Neil SJ, Zang T, Bieniasz PD. Nature. 2008 Jan 24;451(7177):425-30. Epub 2008 Jan 16. PMID: 18200009 [PubMed - indexed for MEDLINE] Related Articles

  8. 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. 2009 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. 2009 Sep 30. [Epub ahead of print] PMID: 19793820 [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. 2009 Sep 9. [Epub ahead of print] PMID: 19740980 [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. 2009 Sep 8;6:80. PMID: 19737401 [PubMed - indexed for MEDLINE] Related ArticlesFree 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. 2009 Sep;5(9):e1000574. Epub 2009 Sep 4. PMID: 19730691 [PubMed - in process] Related ArticlesFree 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. 2009 Sep 2. [Epub ahead of print] PMID: 19726537 [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. 2009 Sep 2. [Epub ahead of print] PMID: 19726508 [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. 2009 Oct;83(19):9672-81. Epub 2009 Jul 15. PMID: 19605472 [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. 2009 Sep;83(17):8771-80. Epub 2009 Jun 24. PMID: 19553332 [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. 2009 Aug;83(16):7931-47. Epub 2009 Jun 10. PMID: 19515779 [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. 2009 Jul 23;6(1):54-67. Epub 2009 Jun 4. PMID: 19501037 [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. 2009 Jun 2;6:53. PMID: 19490609 [PubMed - indexed for MEDLINE] Related ArticlesFree 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. 2009 May;5(5):e1000450. Epub 2009 May 29. PMID: 19478868 [PubMed - indexed for MEDLINE] Related ArticlesFree 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. 2009 Aug;83(15):7536-46. Epub 2009 May 27. PMID: 19474106 [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. 2009 May;5(5):e1000443. Epub 2009 May 22. PMID: 19461879 [PubMed - indexed for MEDLINE] Related ArticlesFree 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. 2009 May;5(5):e1000429. Epub 2009 May 15. PMID: 19436700 [PubMed - indexed for MEDLINE] Related ArticlesFree 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. 2009 Mar 19;5(3):285-97. PMID: 19286137 [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. 2009 May;83(9):4574-90. Epub 2009 Feb 25. PMID: 19244337 [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. 2009 Feb;5(2):e1000300. Epub 2009 Feb 13. PMID: 19214216 [PubMed - indexed for MEDLINE] Related ArticlesFree 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. 2009 Feb 24;106(8):2868-73. Epub 2009 Feb 5. PMID: 19196977 [PubMed - indexed for MEDLINE] Related ArticlesFree 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. 2009 Oct 16. [Epub ahead of print] PMID: 19837671 [PubMed - as supplied by publisher] Related ArticlesFree 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. 2009 Sep 30. [Epub ahead of print] PMID: 19793820 [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. 2009 Sep 9. [Epub ahead of print] PMID: 19740980 [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. 2009 Sep 8;6:80. PMID: 19737401 [PubMed - indexed for MEDLINE] Related ArticlesFree 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. 2009 Sep;5(9):e1000574. Epub 2009 Sep 4. PMID: 19730691 [PubMed - in process] Related ArticlesFree 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. 2009 Sep 2. [Epub ahead of print] PMID: 19726537 [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. 2009 Sep 2. [Epub ahead of print] PMID: 19726508 [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. 2009 Oct;83(19):9672-81. Epub 2009 Jul 15. PMID: 19605472 [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. 2009 Sep;83(17):8771-80. Epub 2009 Jun 24. PMID: 19553332 [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. 2009 Aug;83(16):7931-47. Epub 2009 Jun 10. PMID: 19515779 [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. 2009 Jul 23;6(1):54-67. Epub 2009 Jun 4. PMID: 19501037 [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. 2009 Jun 2;6:53. PMID: 19490609 [PubMed - indexed for MEDLINE] Related ArticlesFree 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. 2009 May;5(5):e1000450. Epub 2009 May 29. PMID: 19478868 [PubMed - indexed for MEDLINE] Related ArticlesFree 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. 2009 Aug;83(15):7536-46. Epub 2009 May 27. PMID: 19474106 [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. 2009 May;5(5):e1000443. Epub 2009 May 22. PMID: 19461879 [PubMed - indexed for MEDLINE] Related ArticlesFree 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. 2009 May;5(5):e1000429. Epub 2009 May 15. PMID: 19436700 [PubMed - indexed for MEDLINE] Related ArticlesFree 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. 2009 Mar 19;5(3):285-97. PMID: 19286137 [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. 2009 May;83(9):4574-90. Epub 2009 Feb 25. PMID: 19244337 [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. 2009 Feb;5(2):e1000300. Epub 2009 Feb 13. PMID: 19214216 [PubMed - indexed for MEDLINE] Related ArticlesFree 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. 2009 Feb 24;106(8):2868-73. Epub 2009 Feb 5. PMID: 19196977 [PubMed - indexed for MEDLINE] Related ArticlesFree article in PMC | at journal site

  9. SUCEPTIBILIDAD A LA INFECCIÓN Y REPLICACIÓN VIRAL Linfocito en reposo Linfocito activado Resistencia a la infección Susceptible a infección Latencia Replicación masiva

  10. 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. 2008 Sep 5;321(5894):1343-6 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. 2006 Apr 17;203(4):865-70. Epub 2006 Apr 10

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

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

  13. Pero las cosas no son fáciles…

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

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

  16. 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).

  17. P P P P DICER PACT TRBP Ago2 Ago2 Ago2 PACT PACT PACT TRBP TRBP TRBP 21-23nt miRNA duplex Cellular miRNAs Nuclear membrane Ago2 Cytosol PACT 4 DICER 1 TRBP Tat DGCR8 Exportin5 Inactive RISC DROSHA miRNA precursors Viral-derived miRNAs (viRNAs) miRISC P Pri-miRNA transcription TAR 4 2 HIV-1 RNA TRBP Host cell DNA Multiple spliced viral mRNA Provirus Active RISC AAAA P Inactive RISC Ago2 PACT miR-28 miR-125b miR-150 miR-223 miR-382 viRNA AAAA 1 Target mRNA 3 Tat/Rev mRNAs AAAA Cellular factor involved in HIV-1 expression 3 Degradation of target mRNA Translational repression RNA DE INTERFERENCIA E INFECCION VIH

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

  19. LATENCIA Y REACTIVACION 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. 2009 Sep;83(17):8470-81. 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. 2009 Jun 9;106(23):9403-8. 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. 2009 Aug;15(8):893-900. Epub 2009 Jun 21 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. 2009 Nov;7(11):798-812.

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

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

  22. Patient 1: Neutralizing HIV Antibody Titers of Sequential Plasma Specimens against Autologous Virus Plasma (months) Virus (months) 0 3 6 9 12 15 18 21 25 Dates 0 26 219 675 1403 2670 2089 2190 2363 2411 9/2/99 3 11/29/99 29 179 1024 2151 3733 3152 2808 2953 3086 6 2/29/00 27 35 78 358 1769 1939 2247 3112 4345 9 5/31/00 36 67 82 200 795 1078 1371 2208 3375 12 8/30/00 19 48 36 64 76 166 556 937 1407 15 11/22/00 29 43 64 76 90 119 374 721 1234 18 2/14/01 42 65 61 152 117 134 122 289 526 21 5/30/01 41 66 82 84 85 113 78 107 296 25 9/11/01 42 62 56 62 85 77 55 61 95 Control NL43 17 138 294 956 1172 953 1584 1868 2143 JRCSF 24 37 35 60 87 97 105 152 209 (D.Richman Rapid evolution of the neutralizing antibody response following primary HIV infection. XIV International AIDS Conference . [Abstract nº1051])

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

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

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

  26. 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 CD4 • 447-52D 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

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

  28. 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 • 447-52D 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

  29. 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.

  30. MAS POLEMICAS: EL PROBLEMA DE LA REDUCCION DE OBJETIVOS ¿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

  31. Microbicidas Fracaso ensayos fase II y III Nueva generaciondemicrobicidas Nuevos mecanismos de liberacion Microbicida oral Walker B. NEJM. 1998 Pilcher CD. J Clin Invest. 2004.

  32. SUJETO DE BERLIN (NUEVO)

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