1887

Abstract

CTLA-4 is a negative regulator of T-cell receptor-mediated CD4 T-cell activation and function. Upregulation of CTLA-4 during human immunodeficiency virus type 1 (HIV-1) infection on activated T cells, particularly on HIV-specific CD4 T cells, correlates with immune dysfunction and disease progression. As HIV-1 infects and replicates in activated CD4 T cells, we investigated mechanisms by which HIV-1 modulates CTLA-4 expression to establish productive viral infection in these cells. Here, we demonstrate that HIV-1 infection in activated CD4 T cells was followed by Nef-mediated downregulation of CTLA-4. This was associated with a decreased T-cell activation threshold and significant resistance to CTLA-4 triggering. In line with these results, quantification of pro-viral HIV DNA from treatment-naive HIV-infected subjects demonstrated a preferential infection of memory CD4CTLA-4 T cells, thus identifying CTLA-4 as a biomarker for HIV-infected cells . As transcriptionally active HIV-1 and Nef expression were previously shown to take place mainly in the CD3CD4CD8 [double-negative (DN)] cells, we further quantified HIV DNA in the CTLA-4 and CTLA-4 subpopulations of these cells. Our results showed that DN T cells lacking CTLA-4 expression were enriched in HIV DNA compared with DN CTLA-4 cells. Together, these results suggested that HIV-1 preferential infection of CD4CTLA-4 T cells was followed by Nef-mediated concomitant downregulation of both CD4 and CTLA-4 upon transition to productive infection. This also highlights the propensity of HIV-1 to evade restriction of the key negative immune regulator CTLA-4 on cell activation and viral replication, and therefore contributes to the overall HIV-1 pathogenesis.

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2015-06-01
2024-12-05
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References

  1. Aiken C., Konner J., Landau N. R., Lenburg M. E., Trono D. 1994; Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell 76:853–864 [View Article][PubMed]
    [Google Scholar]
  2. Arold S. T., Baur A. S. 2001; Dynamic Nef and Nef dynamics: how structure could explain the complex activities of this small HIV protein. Trends Biochem Sci 26:356–363 [View Article][PubMed]
    [Google Scholar]
  3. Azuma M., Yssel H., Phillips J. H., Spits H., Lanier L. L. 1993; Functional expression of B7/BB1 on activated T lymphocytes. J Exp Med 177:845–850 [View Article][PubMed]
    [Google Scholar]
  4. Benson R. E., Sanfridson A., Ottinger J. S., Doyle C., Cullen B. R. 1993; Downregulation of cell-surface CD4 expression by simian immunodeficiency virus Nef prevents viral super infection. J Exp Med 177:1561–1566 [View Article][PubMed]
    [Google Scholar]
  5. Brenchley J. M., Price D. A., Douek D. C. 2006; HIV disease: fallout from a mucosal catastrophe?. Nat Immunol 7:235–239 [View Article][PubMed]
    [Google Scholar]
  6. Brussel A., Sonigo P. 2003; Analysis of early human immunodeficiency virus type 1 DNA synthesis by use of a new sensitive assay for quantifying integrated provirus. J Virol 77:10119–10124 [View Article][PubMed]
    [Google Scholar]
  7. Cecchinato V., Tryniszewska E., Ma Z. M., Vaccari M., Boasso A., Tsai W. P., Petrovas C., Fuchs D., Heraud J. M. et al. 2008; Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection. J Immunol 180:5439–5447 [View Article][PubMed]
    [Google Scholar]
  8. Chen B. K., Gandhi R. T., Baltimore D. 1996; CD4 down-modulation during infection of human T cells with human immunodeficiency virus type 1 involves independent activities of vpu, env, and nef . J Virol 70:6044–6053[PubMed]
    [Google Scholar]
  9. Chomont N., El-Far M., Ancuta P., Trautmann L., Procopio F. A., Yassine-Diab B., Boucher G., Boulassel M. R., Ghattas G. et al. 2009; HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 15:893–900 [View Article][PubMed]
    [Google Scholar]
  10. Cohen G. B., Gandhi R. T., Davis D. M., Mandelboim O., Chen B. K., Strominger J. L., Baltimore D. 1999; The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells. Immunity 10:661–671 [View Article][PubMed]
    [Google Scholar]
  11. Collins K. L., Chen B. K., Kalams S. A., Walker B. D., Baltimore D. 1998; HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391:397–401 [View Article][PubMed]
    [Google Scholar]
  12. Douek D. C., Brenchley J. M., Betts M. R., Ambrozak D. R., Hill B. J., Okamoto Y., Casazza J. P., Kuruppu J., Kunstman K. et al. 2002; HIV preferentially infects HIV-specific CD4+ T cells. Nature 417:95–98 [View Article][PubMed]
    [Google Scholar]
  13. El-Far M., Halwani R., Said E., Trautmann L., Doroudchi M., Janbazian L., Fonseca S., van Grevenynghe J., Yassine-Diab B. et al. 2008; T-cell exhaustion in HIV infection. Curr HIV/AIDS Rep 5:13–19 [View Article][PubMed]
    [Google Scholar]
  14. El-Far M., Isabelle C., Chomont N., Bourbonnière M., Fonseca S., Ancuta P., Peretz Y., Chouikh Y., Halwani R. et al. 2013; Down-regulation of CTLA-4 by HIV-1 Nef protein. PLoS One 8:e54295 [View Article][PubMed]
    [Google Scholar]
  15. Fauré J., Stalder R., Borel C., Sobo K., Piguet V., Demaurex N., Gruenberg J., Trono D. 2004; ARF1 regulates Nef-induced CD4 degradation. Curr Biol 14:1056–1064 [View Article][PubMed]
    [Google Scholar]
  16. Girardi M. 2006; Immunosurveillance and immunoregulation by gammadelta T cells. J Invest Dermatol 126:25–31 [View Article][PubMed]
    [Google Scholar]
  17. Grossman Z., Meier-Schellersheim M., Paul W. E., Picker L. J. 2006; Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nat Med 12:289–295 [View Article][PubMed]
    [Google Scholar]
  18. Guntermann C., Alexander D. R. 2002; CTLA-4 suppresses proximal TCR signaling in resting human CD4+ T cells by inhibiting ZAP-70 Tyr319 phosphorylation: a potential role for tyrosine phosphatases. J Immunol 168:4420–4429 [View Article][PubMed]
    [Google Scholar]
  19. Harlin H., Hwang K. W., Palucki D. A., Kim O., Thompson C. B., Boothby M., Alegre M. L. 2002; CTLA-4 engagement regulates NF-kappaB activation in vivo . Eur J Immunol 32:2095–2104 [View Article][PubMed]
    [Google Scholar]
  20. Jordan M., Schallhorn A., Wurm F. M. 1996; Transfecting mammalian cells: optimization of critical parameters affecting calcium-phosphate precipitate formation. Nucleic Acids Res 24:596–601 [View Article][PubMed]
    [Google Scholar]
  21. Kaiser P., Joos B., Niederöst B., Weber R., Günthard H. F., Fischer M. 2007; Productive human immunodeficiency virus type 1 infection in peripheral blood predominantly takes place in CD4/CD8 double-negative T lymphocytes. J Virol 81:9693–9706 [View Article][PubMed]
    [Google Scholar]
  22. Kaufmann D. E., Walker B. D. 2008; Programmed death-1 as a factor in immune exhaustion and activation in HIV infection. Curr Opin HIV AIDS 3:362–367 [View Article][PubMed]
    [Google Scholar]
  23. Kaufmann D. E., Kavanagh D. G., Pereyra F., Zaunders J. J., Mackey E. W., Miura T., Palmer S., Brockman M., Rathod A. et al. 2007; Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat Immunol 8:1246–1254 [View Article][PubMed]
    [Google Scholar]
  24. Khaitan A., Unutmaz D. 2011; Revisiting immune exhaustion during HIV infection. Curr HIV/AIDS Rep 8:4–11 [View Article][PubMed]
    [Google Scholar]
  25. Kroczek R. A., Mages H. W., Hutloff A. 2004; Emerging paradigms of T-cell co-stimulation. Curr Opin Immunol 16:321–327 [View Article][PubMed]
    [Google Scholar]
  26. Krummel M. F., Allison J. P. 1996; CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med 183:2533–2540 [View Article][PubMed]
    [Google Scholar]
  27. Larsson M., Shankar E. M., Che K. F., Saeidi A., Ellegård R., Barathan M., Velu V., Kamarulzaman A. 2013; Molecular signatures of T-cell inhibition in HIV-1 infection. Retrovirology 10:31 [View Article][PubMed]
    [Google Scholar]
  28. Leng Q., Bentwich Z., Magen E., Kalinkovich A., Borkow G. 2002; CTLA-4 upregulation during HIV infection: association with anergy and possible target for therapeutic intervention. AIDS 16:519–529 [View Article][PubMed]
    [Google Scholar]
  29. Lindwasser O. W., Smith W. J., Chaudhuri R., Yang P., Hurley J. H., Bonifacino J. S. 2008; A diacidic motif in human immunodeficiency virus type 1 Nef is a novel determinant of binding to AP-2. J Virol 82:1166–1174 [View Article][PubMed]
    [Google Scholar]
  30. Little S. J., Riggs N. L., Chowers M. Y., Fitch N. J., Richman D. D., Spina C. A., Guatelli J. C. 1994; Cell surface CD4 downregulation and resistance to superinfection induced by a defective provirus of HIV-1. Virology 205:578–582 [View Article][PubMed]
    [Google Scholar]
  31. Lubben N. B., Sahlender D. A., Motley A. M., Lehner P. J., Benaroch P., Robinson M. S. 2007; HIV-1 Nef-induced down-regulation of MHC class I requires AP-1 and clathrin but not PACS-1 and is impeded by AP-2. Mol Biol Cell 18:3351–3365 [View Article][PubMed]
    [Google Scholar]
  32. Markle T. J., Mwimanzi P., Brockman M. A. 2013; HIV-1 Nef and T-cell activation: a history of contradictions. Future Virol 8:391–404 [View Article][PubMed]
    [Google Scholar]
  33. Mellors J. W., Muñoz A., Giorgi J. V., Margolick J. B., Tassoni C. J., Gupta P., Kingsley L. A., Todd J. A., Saah A. J. et al. 1997; Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 126:946–954 [View Article][PubMed]
    [Google Scholar]
  34. O’Doherty U., Swiggard W. J., Malim M. H. 2000; Human immunodeficiency virus type 1 spinoculation enhances infection through virus binding. J Virol 74:10074–10080 [View Article][PubMed]
    [Google Scholar]
  35. Olivieri K. C., Mukerji J., Gabuzda D. 2011; Nef-mediated enhancement of cellular activation and human immunodeficiency virus type 1 replication in primary T cells is dependent on association with p21-activated kinase 2. Retrovirology 8:64 [View Article][PubMed]
    [Google Scholar]
  36. Pan X., Rudolph J. M., Abraham L., Habermann A., Haller C., Krijnse-Locker J., Fackler O. T. 2012; HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-Golgi network-associated Lck signaling. Blood 119:786–797 [View Article][PubMed]
    [Google Scholar]
  37. Parry R. V., Chemnitz J. M., Frauwirth K. A., Lanfranco A. R., Braunstein I., Kobayashi S. V., Linsley P. S., Thompson C. B., Riley J. L. 2005; CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25:9543–9553 [View Article][PubMed]
    [Google Scholar]
  38. Piguet V., Gu F., Foti M., Demaurex N., Gruenberg J., Carpentier J. L., Trono D. 1999; Nef-induced CD4 degradation: a diacidic-based motif in Nef functions as a lysosomal targeting signal through the binding of beta-COP in endosomes. Cell 97:63–73 [View Article][PubMed]
    [Google Scholar]
  39. Podojil J. R., Miller S. D. 2009; Cross-linking of CD80 on CD4+ T cells activates a calcium-dependent signaling pathway. J Immunol 182:766–773 [View Article][PubMed]
    [Google Scholar]
  40. Riou C., Yassine-Diab B., Van Grevenynghe J., Somogyi R., Greller L. D., Gagnon D., Gimmig S., Wilkinson P., Shi Y. et al. 2007; Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+ central memory T cells. J Exp Med 204:79–91 [View Article][PubMed]
    [Google Scholar]
  41. Roederer M. 2002; Compensation in flow cytometry. Curr Protoc Cytom 22:1.14.1–1.14.20 [View Article][PubMed]
    [Google Scholar]
  42. Rueda C. M., Velilla P. A., Chougnet C. A., Montoya C. J., Rugeles M. T. 2012; HIV-induced T-cell activation/exhaustion in rectal mucosa is controlled only partially by antiretroviral treatment. PLoS One 7:e30307 [View Article][PubMed]
    [Google Scholar]
  43. Sallusto F., Lenig D., Förster R., Lipp M., Lanzavecchia A. 1999; Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401:708–712 [View Article][PubMed]
    [Google Scholar]
  44. Schindler M., Münch J., Kirchhoff F. 2005; Human immunodeficiency virus type 1 inhibits DNA damage-triggered apoptosis by a Nef-independent mechanism. J Virol 79:5489–5498 [View Article][PubMed]
    [Google Scholar]
  45. Schindler M., Münch J., Kutsch O., Li H., Santiago M. L., Bibollet-Ruche F., Müller-Trutwin M. C., Novembre F. J., Peeters M. et al. 2006; Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1. Cell 125:1055–1067 [View Article][PubMed]
    [Google Scholar]
  46. Schneider H., Downey J., Smith A., Zinselmeyer B. H., Rush C., Brewer J. M., Wei B., Hogg N., Garside P., Rudd C. E. 2006; Reversal of the TCR stop signal by CTLA-4. Science 313:1972–1975 [View Article][PubMed]
    [Google Scholar]
  47. Schrager J. A., Marsh J. W. 1999; HIV-1 Nef increases T cell activation in a stimulus-dependent manner. Proc Natl Acad Sci U S A 96:8167–8172 [View Article][PubMed]
    [Google Scholar]
  48. Schwartz O., Maréchal V., Le Gall S., Lemonnier F., Heard J. M. 1996; Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nat Med 2:338–342 [View Article][PubMed]
    [Google Scholar]
  49. Thoulouze M. I., Sol-Foulon N., Blanchet F., Dautry-Varsat A., Schwartz O., Alcover A. 2006; Human immunodeficiency virus type-1 infection impairs the formation of the immunological synapse. Immunity 24:547–561 [View Article][PubMed]
    [Google Scholar]
  50. Trautmann L., Said E. A., Halwani R., Janbazian L., Chomont N., El-Far M., Breton G., Haddad E. K., Sekaly R. P. 2007; Programmed death 1: a critical regulator of T-cell function and a strong target for immunotherapies for chronic viral infections. Curr Opin HIV AIDS 2:219–227 [View Article][PubMed]
    [Google Scholar]
  51. Williams M., Roeth J. F., Kasper M. R., Fleis R. I., Przybycin C. G., Collins K. L. 2002; Direct binding of human immunodeficiency virus type 1 Nef to the major histocompatibility complex class I (MHC-I) cytoplasmic tail disrupts MHC-I trafficking. J Virol 76:12173–12184 [View Article][PubMed]
    [Google Scholar]
  52. Wu Y., Marsh J. W. 2001; Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Science 293:1503–1506 [View Article][PubMed]
    [Google Scholar]
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