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Synapses, cell-to-cell HIV transmission

Fundació. irsiCaixa. Fundació. Fundació. irsiCaixa. irsiCaixa. Synapses, cell-to-cell HIV transmission. Julià Blanco. www.irsicaixa.org. One virus + one cell = ?. ?. Por qué sinapsis??.

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Synapses, cell-to-cell HIV transmission

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  1. Fundació irsiCaixa Fundació Fundació irsiCaixa irsiCaixa Synapses, cell-to-cell HIV transmission Julià Blanco www.irsicaixa.org

  2. One virus + one cell = ? ?

  3. Por qué sinapsis?? • Las sinapsis son uniones estables de dos células mediadas por interacciones específicas que permiten el intercambio de material o información • El tejido linfoide es el principal lugar de replicación del VIH • Alta concentración de células presentadoras (DC, infectadas) y células diana.

  4. Synapses in the immune system MAIN MECHANISM OF COMMUNICATION IN THE IMMUNE SYSTEM - Antigen presentation Threshold for activation - Activation induced death Only cell-surface expressed FAS Is relevant for in vivo cell killing. - CTL recognition of target cells - NK recognition of target cells …

  5. Synapses and viruses Viruses are professional cellular hijackers: VIRUSES EXPLOIT CELLULAR COMUNICATION IN ITS OWN BENEFIT For many viruses, cell-to-cell virus transmission is the most efficient mechanism of viral spread. HTLV-1, first virological synapse defined. Igakura et al. Science 2003, 299:1713-1716.

  6. A role for synapses in HIV infection T cell-Epithelial cell contact HIV transmission HIV spread DC-T cell contact T cell-T cell contact For HIV, cell-to-cell contacts are involved in 90% of infection events in vivo. (Dixit and Perelson, 2004, J Virol)

  7. 1. T cell-Epithelial cell contacts

  8. 2. DC-T cell contacts. Infectious synapse.

  9. DC-SIGN independent HIV capture.

  10. Virus and exosomes. Izquierdo-Useros N, Naranjo M et al, BLOOD 2009

  11. CD4 CXCR4 Env Env 3. T cell-t cell contacts. Virological synapses. Morphologically similar to other synapses. Joly C. et al. JEM 2004, 199:283-293 Main determinant: gp120-CD4 interaction. Adhesion molecules, secondary role(Puigdomènech et al RETROVIROLOGY, 2008. 5:32) HIV ENV ICAM-1 ICAM-1 HIV ENV LFA-1 CD4 CD4 LFA-1 CXCR4 CCR5 CXCR4 CCR5

  12. Pero las cosas no son fáciles…

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

  14. Infected - uninfected cellular contacts Conjugate Formation A role for trogocytosis? Effect on inhibition/neutralization? Hemifusion/ Target cell death Cell-to-cell Fusion Target cell infection

  15. * * * * C34 C34 3100 3100 Ctrl + Ctrl + Leu3a Leu3a TAK779 TAK779 SHAKING SHAKING NL4-3 BaL 20 20 15 15 Conjugated CD4 T Cells (%) Conjugated CD4 T Cells (%) 10 10 5 5 0 0 Formation of cellular conjugates. Infected cells Target cells UNINF NL4-3 BaL Control Leu3a Shaking 1% 13% 8% 2% 1% 1% 1% 1% 1% FSC * * * * 2F5 2F5 C34 C34 4E10 4E10 Ctrl + Ctrl + Leu3a Leu3a IgGb12 IgGb12 CMRA NL4-3 (X4) BaL (R5)

  16. Transport of viral materials (p24) CD4+ CXCR4+ CCR5- X4 R5

  17. Transport of viral materials (p24) INFECTON (TRANSMISSION) PASSIVE TRANSFER

  18. Accumulation of HIV into endosomes * * * * * * * *

  19. CD4-GFP+ MOLT Cells (%) NL4-3 BaL Transport of membranes. Trogocytosis % MOLT CD4-GFP+ UNINFECTED INFECTED 2h 293-CD4GFP+ MOLT NL4-3/BaL Trogocytosis at the VS is Fusion-independent CD4-dependent

  20. NL4-3 wt NL4-3 wt 41.2 41.2 Transport of membranes. Trogocytosis • How to measure membrane transfer? • No fusogenic activity to avoid hemifusion • No virus production to avoid transfer of virus • Expression of Env mutant 41.2 INFECTED UNINFECTED 293(Env+Denv) 24h 293(Env) 24h CD4 % CD4 p24 + CD4 % CD4 DiI +

  21. Infected - uninfected cellular contacts CD4 blockade Conjugate Formation Virus Transfer Membrane Exchange CD4 engagement Coreceptor or gp41 blockade Hemifusion/ Target cell death Cell-to-cell Fusion Target cell infection Gp41 activation

  22. Fundació irsiCaixa * Infection 24h Real-Time PCR (probes for HIV and CCR5) To test active retrotranscription

  23. Fundació irsiCaixa Virological Synapse Target cell Infected cell

  24. Conclusions. Synapses increase the efficiency of HIV transmission/spread. Two major synaptic mechanisms are involved in HIV spread: Infectious (DC-T cell) (virus hides in DCs) Virological (T cell-T cell) synapses (virus-driven) For virological synapses: Cell-to-cell HIV transmission requires an extracellular neutralization-sensitive step. Implications for vaccine design. Pathophysiological consequences…

  25. Fundació irsiCaixa I. Puigdomènech M. Massanella M. Curriu F. Cuñat E. García S. Marfil J. Carrillo C. Cabrera Margarita Bofill Nuria Izquierdo-Useros Javier Martínez-Picado Bonaventura Clotet Hospital Clínic (Barcelona) Manel Juan Hospital Germans Trias Maria T. Fernández IPBS (Toulouse) A. Aucher G. Gaibelet D. Hudrisier

  26. Fundació irsiCaixa I. Puigdomènech M. Massanella M. Curriu F. Cuñat E. García S. Marfil J. Carrillo C. Cabrera Margarita Bofill Nuria Izquierdo-Useros Javier Martínez-Picado Bonaventura Clotet Hospital Clínic (Barcelona) Manel Juan Hospital Germans Trias Maria T. Fernández IPBS (Toulouse) A. Aucher G. Gaibelet D. Hudrisier

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