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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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slide1

I.P.

RESUMEN DE LOS AVANCES EN

INVESTIGACIÓN BÁSICA

Pepe Alcami

Unidad de Inmunopatologia del SIDA

Instituto de SaIud Carlos III

slide2

I.P.

CD4

  • Virologia
    • Factores celulares
    • Nuevos mecanismos de entrada
    • Latencia Reactivación
  • Inmunologia
    • Celulas T reguladoras
    • Vacunas
  • Casos especiales
slide3

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

slide4

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

slide5

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.

slide6

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.

slide7

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

slide10

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

slide11

SUCEPTIBILIDAD A LA INFECCIÓN Y REPLICACIÓN VIRAL

Linfocito en reposo Linfocito activado

Resistencia a la infección Susceptible a infección Latencia Replicación masiva

slide12

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

slide13

I.P.

CD4

  • Virologia
    • Factores celulares
    • Nuevos mecanismos de entrada
    • Latencia Reactivación
  • Inmunologia
    • Celulas T reguladoras
    • Vacunas
  • Casos especiales
slide14

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

slide18

Trogocytosis…

Intercellular exchange of antigens/membranes.

Active process of cellular communication, different from proteolitic cleavage or exosome transfer.

slide19

I.P.

CD4

  • Virologia
    • Factores celulares
    • Nuevos mecanismos de entrada
    • Latencia Reactivación
  • Inmunologia
    • Celulas T reguladoras
    • Vacunas
  • Casos especiales
slide20

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).
slide21

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

slide22

+

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

slide23

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.

slide24

I.P.

CD4

  • Virologia
    • Factores celulares
    • Nuevos mecanismos de entrada
    • Latencia Reactivación
  • Inmunologia
    • Celulas T reguladoras
    • Vacunas
  • Casos especiales
slide25

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])

slide26

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])

slide27

EL GRAN DESAFIO: OBTENER ANTICUERPOS NEUTRALIZANTES

Karlsson et al. Nat.Rev.Microbiol 2008

antibody induction reverse vaccinology
Antibody inductionReverse Vaccinology

(Burton D. Human neutralizing antibodies and a vaccine for HIV-1.

XIV International AIDS Conference [Abstract nº201])

slide29

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
slide30

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
slide31

Structure of b12 neutralising antibody

(Burton D. Human neutralizing antibodies and a vaccine for HIV-1.

XIV International AIDS Conference [Abstract nº201])

slide32

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

slide33

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.
qu podemos esperar de una vacuna frente al vih

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

slide36

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.