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HIV-1 envelope protein binds to and signals through integrin α4β7, the gut mucosal homing receptor for peripheral T cells

Abstract

Infection with human immunodeficiency virus 1 (HIV-1) results in the dissemination of virus to gut-associated lymphoid tissue. Subsequently, HIV-1 mediates massive depletion of gut CD4+ T cells, which contributes to HIV-1-induced immune dysfunction. The migration of lymphocytes to gut-associated lymphoid tissue is mediated by integrin α4β7. We demonstrate here that the HIV-1 envelope protein gp120 bound to an activated form of α4β7. This interaction was mediated by a tripeptide in the V2 loop of gp120, a peptide motif that mimics structures presented by the natural ligands of α4β7. On CD4+ T cells, engagement of α4β7 by gp120 resulted in rapid activation of LFA-1, the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1.

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Figure 1: Binding of gp120 to α4β7 on NK cells.
Figure 2: Integrin α4β7 mediates CD4-independent binding of gp120 on retinoic acid?treated T cells.
Figure 3: Binding to α4β7 uses a Leu-Asp-Val sequence in the gp120 V2 loop.
Figure 4: Sequence conservation of the α4β7-binding motif in the V2 loop of HIV-1.
Figure 5: Binding of gp120 to α4β7 activates LFA-1.
Figure 6: Integrin α4β7 localizes together with active LFA-1 and CD4 at the interface of adhesive junctions.
Figure 7: Reversion of a Leu-Asp-Val?mutant HIV-1 provirus results in enhanced sensitivity to gp120-α4β7 antagonists.

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References

  1. Brenchley, J.M., Price, D.A. & Douek, D.C. HIV disease: fallout from a mucosal catastrophe? Nat. Immunol. 7, 235?239 (2006).

    Article  CAS  Google Scholar 

  2. Brenchley, J.M. et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J. Exp. Med. 200, 749?759 (2004).

    Article  CAS  Google Scholar 

  3. Guadalupe, M. et al. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J. Virol. 77, 11708?11717 (2003).

    Article  CAS  Google Scholar 

  4. Li, Q. et al. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 434, 1148?1152 (2005).

    Article  CAS  Google Scholar 

  5. Mattapallil, J.J. et al. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 434, 1093?1097 (2005).

    Article  CAS  Google Scholar 

  6. Veazey, R.S. et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280, 427?431 (1998).

    Article  CAS  Google Scholar 

  7. Haase, A.T. Perils at mucosal front lines for HIV and SIV and their hosts. Nat. Rev. Immunol. 5, 783?792 (2005).

    Article  CAS  Google Scholar 

  8. Picker, L.J. Immunopathogenesis of acute AIDS virus infection. Curr. Opin. Immunol. 18, 399?405 (2006).

    Article  CAS  Google Scholar 

  9. von Andrian, U.H. & Mackay, C.R. T-cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343, 1020?1034 (2000).

    Article  CAS  Google Scholar 

  10. Wagner, N. et al. Critical role for β7 integrins in formation of the gut-associated lymphoid tissue. Nature 382, 366?370 (1996).

    Article  CAS  Google Scholar 

  11. Kottilil, S. et al. Innate immune dysfunction in HIV infection: effect of HIV envelope-NK cell interactions. J. Immunol. 176, 1107?1114 (2006).

    Article  CAS  Google Scholar 

  12. Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527?538 (2004).

    Article  CAS  Google Scholar 

  13. Zeller, Y., Mechtersheimer, S. & Altevogt, P. Critical amino acid residues of the α4 subunit for α4β7 integrin function. J. Cell. Biochem. 83, 304?319 (2001).

    Article  CAS  Google Scholar 

  14. Schiffer, S.G., Hemler, M.E., Lobb, R.R., Tizard, R. & Osborn, L. Molecular mapping of functional antibody binding sites of α4 integrin. J. Biol. Chem. 270, 14270?14273 (1995).

    Article  CAS  Google Scholar 

  15. Schweighoffer, T. et al. Selective expression of integrin α4β7 on a subset of human CD4+ memory T cells with hallmarks of gut-trophism. J. Immunol. 151, 717?729 (1993).

    CAS  PubMed  Google Scholar 

  16. Jackson, D.Y. Alpha 4 integrin antagonists. Curr. Pharm. Des. 8, 1229?1253 (2002).

    Article  CAS  Google Scholar 

  17. Vanderslice, P. et al. A cyclic hexapeptide is a potent antagonist of α4 integrins. J. Immunol. 158, 1710?1718 (1997).

    CAS  PubMed  Google Scholar 

  18. Park, S.I. The use of one-bead one-compound combinatorial library method to identify peptide ligands for α4β1 integrin receptor in non-Hodgkin's lymphoma. Lett. Pept. Sci. 8, 171?178 (2002).

    Google Scholar 

  19. Harouse, J.M. et al. Mucosal transmission and induction of simian AIDS by CCR5-specific simian/human immunodeficiency virus SHIV(SF162P3). J. Virol. 75, 1990?1995 (2001).

    Article  CAS  Google Scholar 

  20. Harouse, J.M., Gettie, A., Tan, R.C., Blanchard, J. & Cheng-Mayer, C. Distinct pathogenic sequela in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs. Science 284, 816?819 (1999).

    Article  CAS  Google Scholar 

  21. Ho, S.H., Shek, L., Gettie, A., Blanchard, J. & Cheng-Mayer, C. V3 loop-determined coreceptor preference dictates the dynamics of CD4+-T-cell loss in simian-human immunodeficiency virus-infected macaques. J. Virol. 79, 12296?12303 (2005).

    Article  CAS  Google Scholar 

  22. Harouse, J.M. et al. Pathogenic determinants of the mucosally transmissible CXCR4-specific SHIV(SF33A2) map to env region. J. Acquir. Immune Defic. Syndr. 27, 222?228 (2001).

    Article  CAS  Google Scholar 

  23. Bargatze, R.F., Jutila, M.A. & Butcher, E.C. Distinct roles of L-selectin and integrins α4 β7 and LFA-1 in lymphocyte homing to Peyer's patch-HEV in situ: the multistep model confirmed and refined. Immunity 3, 99?108 (1995).

    Article  CAS  Google Scholar 

  24. Chan, J.R., Hyduk, S.J. & Cybulsky, M.I. α4β1 integrin/VCAM-1 interaction activates αLβ2 integrin-mediated adhesion to ICAM-1 in human T cells. J. Immunol. 164, 746?753 (2000).

    Article  CAS  Google Scholar 

  25. Bromley, S.K. et al. The immunological synapse. Annu. Rev. Immunol. 19, 375?396 (2001).

    Article  CAS  Google Scholar 

  26. Piguet, V. & Sattentau, Q. Dangerous liaisons at the virological synapse. J. Clin. Invest. 114, 605?610 (2004).

    Article  CAS  Google Scholar 

  27. Jolly, C., Kashefi, K., Hollinshead, M. & Sattentau, Q.J. HIV-1 cell to cell transfer across an Env-induced, actin-dependent synapse. J. Exp. Med. 199, 283?293 (2004).

    Article  CAS  Google Scholar 

  28. Fortin, J.F., Cantin, R. & Tremblay, M.J. T cells expressing activated LFA-1 are more susceptible to infection with human immunodeficiency virus type 1 particles bearing host-encoded ICAM-1. J. Virol. 72, 2105?2112 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Drbal, K., Angelisova, P., Cerny, J., Hilgert, I. & Horejsi, V. A novel anti-CD18 mAb recognizes an activation-related epitope and induces a high-affinity conformation in leukocyte integrins. Immunobiology 203, 687?698 (2001).

    Article  CAS  Google Scholar 

  30. Sourisseau, M., Sol-Foulon, N., Porrot, F., Blanchet, F. & Schwartz, O. Inefficient human immunodeficiency virus replication in mobile lymphocytes. J. Virol. 81, 1000?1012 (2007).

    Article  CAS  Google Scholar 

  31. Daar, E.S., Li, X.L., Moudgil, T. & Ho, D.D. High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates. Proc. Natl. Acad. Sci. USA 87, 6574?6578 (1990).

    Article  CAS  Google Scholar 

  32. Tardif, M.R. & Tremblay, M.J. LFA-1 is a key determinant for preferential infection of memory CD4+ T cells by human immunodeficiency virus type 1. J. Virol. 79, 13714?13724 (2005).

    Article  CAS  Google Scholar 

  33. Juszczak, R.J., Turchin, H., Truneh, A., Culp, J. & Kassis, S. Effect of human immunodeficiency virus gp120 glycoprotein on the association of the protein tyrosine kinase p56lck with CD4 in human T lymphocytes. J. Biol. Chem. 266, 11176?11183 (1991).

    CAS  PubMed  Google Scholar 

  34. Weissman, D. et al. Macrophage-tropic HIV and SIV envelope proteins induce a signal through the CCR5 chemokine receptor. Nature 389, 981?985 (1997).

    Article  CAS  Google Scholar 

  35. Cicala, C. et al. Induction of phosphorylation and intracellular association of CC chemokine receptor 5 and focal adhesion kinase in primary human CD4+ T cells by macrophage-tropic HIV envelope. J. Immunol. 163, 420?426 (1999).

    CAS  PubMed  Google Scholar 

  36. Kwong, P.D. et al. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature 420, 678?682 (2002).

    Article  CAS  Google Scholar 

  37. Zhou, T. et al. Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature 445, 732?737 (2007).

    Article  CAS  Google Scholar 

  38. Mehandru, S. et al. Mechanisms of gastrointestinal CD4+ T-cell depletion during acute and early human immunodeficiency virus type 1 infection. J. Virol. 81, 599?612 (2007).

    Article  CAS  Google Scholar 

  39. Tardif, M.R. & Tremblay, M.J. Regulation of LFA-1 activity through cytoskeleton remodeling and signaling components modulates the efficiency of HIV type-1 entry in activated CD4+ T lymphocytes. J. Immunol. 175, 926?935 (2005).

    Article  CAS  Google Scholar 

  40. Davenport, R.J. & Munday, J.R. Alpha4-integrin antagonism?an effective approach for the treatment of inflammatory diseases? Drug Discov. Today 12, 569?576 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Shaw, G. Snyder, T.-W. Chun, A. Kinter and S. Moir for discussions; J.I. Mullins for providing the AN1 coding sequence; J. Weddle for figure preparation; and the National Institutes of Health AIDS Research and Reference Reagent Program for many reagents. Act-1 was provided by S. Shaw (National Cancer Institute), and NL43-SF162 was provided by R.L. Willey (National Institute of Allergy and Infectious Diseases). Supported by the National Institutes of Health (AI058894 and AI047734 to S.M.; and the Intramural Research Program).

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D.J.G., K.M., E.M., C.C., J.M., M.P., D.W., S.K., C.C.C., N.C., E.C., K.N.R. and D.V.R. did biological experiments; Z.X., T.D.V., T.P.C. and R.A.L. did proteomic and bioinformatics analyses; J.A., C.C., E.M. and A.S.F. conceived and designed experiments; and all authors participated in manuscript preparation.

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Correspondence to James Arthos.

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Arthos, J., Cicala, C., Martinelli, E. et al. HIV-1 envelope protein binds to and signals through integrin α4β7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol 9, 301–309 (2008). https://doi.org/10.1038/ni1566

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