1887

Abstract

Sexual transmission is now the most frequent means of diffusion of human immunodeficiency virus type 1 (HIV-1). Even if the underlying mechanism is still largely unknown, there is a consensus regarding the key role played by mucosal dendritic cells (DCs) in capturing HIV through contact with infected subepithelial lymphocytes, and their capacity to spread HIV by -infection. We found that HIV protease inhibitors (PIs) reduced virion endocytosis strongly in monocyte-derived immature (i) DCs contacting HIV-1-infected cells, and that this phenomenon led to dramatically impaired -infection activity. This inhibitory effect was not mediated by the block of viral protease activity, as it was also operative when donor cells were infected with a PI-resistant HIV-1 strain. The block of virus maturation imposed by PIs did not correlate with significant variations in the levels of virus expression in donor cells or of Gag/Env virion incorporation. Also, PIs did not affect the endocytosis activity of DCs. In contrast, we noticed that PI treatment inhibited the formation of cell–cell conjugates whilst reducing the expression of ICAM-1 in target iDCs. Our results contribute to a better delineation of the mechanisms underlying HIV-1 -infection activity in DCs, whilst having implications for the development of new anti-HIV microbicide strategies.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.012609-0
2009-11-01
2019-11-14
Loading full text...

Full text loading...

/deliver/fulltext/jgv/90/11/2777.html?itemId=/content/journal/jgv/10.1099/vir.0.012609-0&mimeType=html&fmt=ahah

References

  1. Bomsel, M. ( 1997; ). Transcytosis of infectious human immunodeficiency virus across a tight human epithelial cell line barrier. Nat Med 3, 42–47.[CrossRef]
    [Google Scholar]
  2. Bouschbacher, M., Bomsel, M., Verronèse, E., Gofflo, S., Ganor, Y., Dezutter-Dambuyant, C. & Valladeau, J. ( 2008; ). Early events in HIV transmission through a human reconstructed vaginal mucosa. AIDS 22, 1257–1266.[CrossRef]
    [Google Scholar]
  3. Cavrois, M., Neidleman, J., Kreisberg, J. F. & Greene, W. C. ( 2007; ). In vitro derived dendritic cells trans-infect CD4 T cells primarily with surface-bound HIV-1 virions. PLoS Pathog 3, e4 [CrossRef]
    [Google Scholar]
  4. Cavrois, M., Neidleman, J. & Greene, W. C. ( 2008; ). The Achilles heel of the Trojan horse model of HIV-1 trans-infection. PLoS Pathog 4, e1000051 [CrossRef]
    [Google Scholar]
  5. Chen, P., Hubner, W., Spinelli, M. A. & Chen, B. K. ( 2007; ). Predominant mode of human immunodeficency virus transfer between T cells is mediated by sustained Env-dependent neutralization-resistant virological synapses. J Virol 81, 12582–12595.[CrossRef]
    [Google Scholar]
  6. Collins, K. B., Patterson, B. K., Naus, G. J., Landers, D. V. & Gupta, P. ( 2000; ). Development of an in vitro organ culture model to study transmission of HIV-1 in the female genital tract. Nat Med 6, 475–479.[CrossRef]
    [Google Scholar]
  7. Condra, J. H., Schleif, W. A., Blahy, O. M., Gabryelski, L. J., Graham, D. J., Quintero, J. C., Rhodes, A., Robbins, H. L., Roth, E. & other authors ( 1995; ). In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 374, 569–571.[CrossRef]
    [Google Scholar]
  8. Eugenin, E. A., Gaskill, P. J. & Berman, J. W. ( 2009; ). Tunneling nanotubes (TNT) are induced by HIV-infection of macrophages: a potential mechanism for intercellular HIV trafficking. Cell Immunol 254, 142–148.[CrossRef]
    [Google Scholar]
  9. Flexner, C. ( 1998; ). HIV-protease inhibitors. N Engl J Med 338, 1281–1292.[CrossRef]
    [Google Scholar]
  10. Garcia, E., Pion, M., Pelchen-Matthews, A., Collinson, L., Arrighi, J. F., Blot, G., Leuba, F., Escola, J. M., Demaurex, M. & other authors ( 2005; ). HIV-1 trafficking to the dendritic cell-T-cell infectious synapse uses a pathway of tetraspanin sorting to the immunological synapse. Traffic 6, 488–501.[CrossRef]
    [Google Scholar]
  11. Geijtenbeek, T. B., Kwon, D. S., Torensma, R., van Vliet, S. J., van Duijnhoven, G. C., Middel, J., Cornelissen, I. L., Nottet, H. S., Kewal-Ramani, V. N. & other authors ( 2000; ). DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100, 587–597.[CrossRef]
    [Google Scholar]
  12. Gervaix, A., West, D., Leoni, L. M., Richman, D. D., Wong-Staal, F. & Corbeil, J. ( 1997; ). A new reporter cell line to monitor HIV infection and drug susceptibility in vitro. Proc Natl Acad Sci U S A 94, 4653–4658.[CrossRef]
    [Google Scholar]
  13. Gousset, K., Ablan, S. D., Coren, L. V., Ono, A., Soheilian, F., Nagashima, K., Ott, D. E. & Freed, E. O. ( 2008; ). Real-time visualization of HIV-1 GAG trafficking in infected macrophages. PLoS Pathog 4, e1000015 [CrossRef]
    [Google Scholar]
  14. Groot, F., Welsch, S. & Sattentau, Q. J. ( 2008; ). Efficient HIV-1 transmission from macrophages to T cells across transient virological synapses. Blood 111, 4660–4663.[CrossRef]
    [Google Scholar]
  15. Gupta, P., Collins, K. B., Ratner, D., Watkins, S., Naus, G. J., Landers, D. V. & Patterson, B. K. ( 2002; ). Memory CD4+ T cells are the earliest detectable human immunodeficiency virus type 1 (HIV-1)-infected cells in the female genital mucosal tissue during HIV-1 transmission in an organ culture system. J Virol 76, 9868–9876.[CrossRef]
    [Google Scholar]
  16. Haase, A. T. ( 2005; ). Perils at mucosal front lines for HIV and SIV and their hosts. Nat Rev Immunol 5, 783–792.[CrossRef]
    [Google Scholar]
  17. Hladik, F. & McElrath, M. J. ( 2008; ). Setting the stage: host invasion by HIV. Nat Rev Immunol 8, 447–457.[CrossRef]
    [Google Scholar]
  18. Hladik, F., Sakchalathorn, P., Ballweber, L., Lentz, G., Fialkow, M., Eschenbach, D. & McElrath, M. J. ( 2007; ). Initial events in establishing vaginal entry and infection by human immunodeficiency virus type-1. Immunity 26, 257–270.[CrossRef]
    [Google Scholar]
  19. Hu, J., Gardner, M. B. & Miller, C. J. ( 2000; ). Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells. J Virol 74, 6087–6095.[CrossRef]
    [Google Scholar]
  20. Jolly, C., Kashefi, K., Hollinshead, M. & Sattentau, Q. J. ( 2004; ). HIV-1 cell to cell transfer across an Env-induced, actin-dependent synapse. J Exp Med 199, 283–293.[CrossRef]
    [Google Scholar]
  21. Kaplan, A. H., Zack, J. A., Knigge, M., Paul, D. A., Kempf, D. J., Norbeck, D. W. & Swanstrom, R. ( 1993; ). Partial inhibition of the human immunodeficiency virus type 1 protease results in aberrant virus assembly and the formation of noninfectious particles. J Virol 67, 4050–4055.
    [Google Scholar]
  22. Kawamura, T., Cohen, S. S., Borris, D. L., Aquilino, E. A., Glushakova, S., Margolis, L. B., Ornestein, J. M., Offord, R. E., Neurath, A. R. & Blauvelt, A. ( 2000; ). Candidate microbicides block HIV-1 infection of human immature Langerhans cells within epithelial tissue explants. J Exp Med 192, 1491–1500.[CrossRef]
    [Google Scholar]
  23. Kilby, J. M., Hopkins, S., Venetta, T. M., Di Massimo, B., Cloud, G. A., Lee, J. Y., Alldredge, L., Hunter, E., Lambert, D. & other authors ( 1998; ). Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 4, 1302–1307.[CrossRef]
    [Google Scholar]
  24. McDonald, D., Wu, L., Bohks, S. M., Kewal Ramani, V. N., Unutmaz, D. & Hope, T. J. ( 2003; ). Recruitment of HIV and its receptors to dendritic cell-T cell junctions. Science 300, 1295–1297.[CrossRef]
    [Google Scholar]
  25. Muratori, C., D'Aloja, P., Superti, F., Tinari, A., Sol-Foulon, N., Sparacio, S., Bosch, V., Schwartz, O. & Federico, M. ( 2006; ). Generation and characterization of a stable cell population releasing fluorescent HIV-1-based virus like particles in an inducible way. BMC Biotechnol 6, 52 [CrossRef]
    [Google Scholar]
  26. Muratori, C., Bona, R., Ruggiero, E., D'Ettorre, G., Vullo, V., Andreotti, M. & Federico, M. ( 2009; ). DC contact with HIV-1-infected cells leads to high levels of Env-mediated virion endocytosis coupled with enhanced HIV-1 Ag presentation. Eur J Immunol 39, 404–416.[CrossRef]
    [Google Scholar]
  27. Piguet, V. & Steinman, R. M. ( 2007; ). The interaction of HIV with dendritic cells: outcomes and pathways. Trends Immunol 28, 503–510.[CrossRef]
    [Google Scholar]
  28. Rudnicka, D., Feldmann, J., Porrot, F., Wietgrefe, S., Guadagnini, S., Prévost, M. C., Estaquier, J., Haase, A. T., Sol-Foulon, N. & other authors ( 2009; ). Simultaneous cell-to-cell transmission of human immunodeficiency virus to multiple targets through polysynapses. J Virol 83, 6234–6246.[CrossRef]
    [Google Scholar]
  29. Ruggiero, E., Bona, R., Muratori, C. & Federico, M. ( 2008; ). Virological consequences of early events following cell-cell contact between human immunodeficiency virus type 1-infected and uninfected CD4+ cells. J Virol 82, 7773–7789.[CrossRef]
    [Google Scholar]
  30. Schatzl, H., Gelderblom, H. R., Nitschko, H. & von der Helm, K. ( 1991; ). Analysis of non-infectious HIV particles produced in presence of HIV proteinase inhibitor. Arch Virol 120, 71–81.[CrossRef]
    [Google Scholar]
  31. Sekaly, R. P. ( 2008; ). The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development? J Exp Med 205, 7–12.[CrossRef]
    [Google Scholar]
  32. Sherer, N. M., Lehmann, M. J., Jimenez-Soto, L. F., Horensavitz, C., Pypaert, M. & Mothes, W. ( 2007; ). Retroviruses can establish filopodial bridges for efficient cell-to-cell transmission. Nat Cell Biol 9, 310–315.[CrossRef]
    [Google Scholar]
  33. Sourisseau, M., Sol-Foulon, N., Porrot, F., Blanchet, F. & Schwartz, O. ( 2007; ). Inefficient human immunodeficiency virus replication in mobile lymphocytes. J Virol 81, 1000–1012.[CrossRef]
    [Google Scholar]
  34. Sowinski, S., Jolly, C., Berninghausen, O., Purbhoo, M. A., Chauveau, A., Kohler, K., Oddos, S., Eissmann, P., Brodsky, F. M. & other authors ( 2008; ). Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission. Nat Cell Biol 10, 211–219.[CrossRef]
    [Google Scholar]
  35. Sparacio, S., Pfeiffer, T., Schaal, H. & Bosch, V. ( 2001; ). Generation of a flexible cell line with regulatable, high-level expression of HIV Gag/Pol particles capable of packaging HIV-derived vectors. Mol Ther 3, 602–612.[CrossRef]
    [Google Scholar]
  36. Spira, A. I., Marx, P. A., Patterson, B. K., Mahoney, J., Koup, R. A., Wolinsky, S. M. & Ho, D. D. ( 1996; ). Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J Exp Med 183, 215–225.[CrossRef]
    [Google Scholar]
  37. Tan, X. & Phillips, D. M. ( 1996; ). Cell-mediated infection of cervix derived epithelial cells with primary isolates of human immunodeficiency virus. Arch Virol 141, 1177–1189.[CrossRef]
    [Google Scholar]
  38. Turville, S. G., Santos, J. J., Frank, I., Cameron, P. U., Wilkinson, J., Miranda-Saksena, M., Dable, J., Stossel, H., Romani, N. & other authors ( 2004; ). Immunodeficiency virus uptake, turnover, and 2-phase transfer in human dendritic cells. Blood 103, 2170–2179.[CrossRef]
    [Google Scholar]
  39. Van Damme, L., Govinden, R., Mirembe, F. M., Guédou, F., Solomon, S., Becker, L., Pradeep, B. S., Krishan, A. K., Alary, M. & other authors ( 2008; ). Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission. N Engl J Med 359, 463–472.[CrossRef]
    [Google Scholar]
  40. Wiley, R. D. & Gummuluru, S. ( 2006; ). Immature dendritic cell-derived exosomes can mediate HIV-1 trans infection. Proc Natl Acad Sci U S A 103, 738–743.[CrossRef]
    [Google Scholar]
  41. Wu, L. ( 2008; ). Biology of HIV mucosal transmission. Curr Opin HIV AIDS 3, 534–540.[CrossRef]
    [Google Scholar]
  42. Yu, H. J., Reuter, M. A. & McDonald, D. ( 2008; ). HIV traffics through a specialized, surface-accessible intracellular compartment during trans-infection of T cells by mature dendritic cells. PLoS Pathog 4, e1000134 [CrossRef]
    [Google Scholar]
  43. Zhang, Z., Schuler, T., Zupancic, M., Wietgrefe, S., Staskus, K. A., Reimann, T. A., Reinhart, T. A., Rogan, M., Cavert, C. J. & other authors ( 1999; ). Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 286, 1353–1357.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.012609-0
Loading
/content/journal/jgv/10.1099/vir.0.012609-0
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error