1887

Abstract

The pathogenic Nef protein of the human immunodeficiency virus type 1 (HIV-1) downregulates CD4 by inducing its endocytosis and by inhibiting the transport of the receptor to the cell membrane. By means of -selected mutations, we show that L37, P78 and E177 residues of Nef are required for its effect on CD4 internalization and recycling but dispensable for Nef-induced retention and degradation of intracellular CD4. Of note, the function of Nef on the anterograde transport of newly synthesized CD4 molecules is irrelevant in cells with a slow constitutive CD4 turnover such as T cell lines. Moreover, we show that a mutated CD4 that is unresponsive to Nef-mediated endocytosis, CD4LLAA, is retained intracellularly and degraded by Nef like wild-type CD4. Thus, Nef's abilities to enhance endocytosis and induce intracellular retention of CD4 are mediated by separate protein surfaces and occur through distinct mechanisms.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.83164-0
2007-11-01
2021-03-03
Loading full text...

Full text loading...

/deliver/fulltext/jgv/88/11/3133.html?itemId=/content/journal/jgv/10.1099/vir.0.83164-0&mimeType=html&fmt=ahah

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 [CrossRef]
    [Google Scholar]
  2. Bentham M., Mazaleyrat S., Harris M. 2003; The di-leucine motif in the cytoplasmic tail of CD4 is not required for binding to human immunodeficiency virus type 1 Nef, but is critical for CD4 down-modulation. J Gen Virol 84:2705–2713 [CrossRef]
    [Google Scholar]
  3. Casartelli N., Di Matteo G., Argentini C., Cancrini C., Bernardi S., Castelli G., Scarlatti G., Plebani A., Rossi P., Doria M. 2003a; Structural defects and variations in the HIV-1 nef gene from rapid, slow and non-progressor children. AIDS 17:1291–1301 [CrossRef]
    [Google Scholar]
  4. Casartelli N., Di Matteo G., Potestà M., Rossi P., Doria M. 2003b; CD4 and major histocompatibility complex class I downregulation by the human immunodeficiency virus type 1 Nef protein in pediatric AIDS progression. J Virol 77:11536–11545 [CrossRef]
    [Google Scholar]
  5. Casartelli N., Giolo G., Neri F., Haller C., Potestà M., Rossi P., Fackler O. T., Doria M. 2006; The Pro78 residue regulates the capacity of the human immunodeficiency virus type 1 Nef protein to inhibit recycling of major histocompatibility complex class I molecules in an SH3-independent manner. J Gen Virol 87:2291–2296 [CrossRef]
    [Google Scholar]
  6. Deacon N. J., Tsykin A., Solomon A., Smith K., Ludford-Menting M., Hooker D. J., McPhee D. A., Greenway A. L., Ellett A. other authors 1995; Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 270:988–991 [CrossRef]
    [Google Scholar]
  7. Fackler O. T., Lu X., Frost J. A., Geyer M., Jiang B., Luo W., Abo A., Alberts A. S., Peterlin B. M. 2000; p21-activated kinase 1 plays a critical role in cellular activation by Nef. Mol Cell Biol 20:2619–2627 [CrossRef]
    [Google Scholar]
  8. Geyer M., Peterlin B. M. 2001; Domain assembly, surface accessibility and sequence conservation in full length HIV-1 Nef. FEBS Lett 496:91–95 [CrossRef]
    [Google Scholar]
  9. Geyer M., Munte C. E., Schorr J., Kellner R., Kalbitzer H. R. 1999; Structure of the anchor-domain of myristoylated and non-myristoylated HIV-1 Nef protein. J Mol Biol 289:123–138 [CrossRef]
    [Google Scholar]
  10. Geyer M., Fackler O. T., Peterlin B. M. 2001; Structure-function relationships in HIV-1 Nef. EMBO Rep 2:580–585 [CrossRef]
    [Google Scholar]
  11. Greenberg M. E., Bronson S., Lock M., Neumann M., Pavlakis G. N., Skowronski J. 1997; Co-localization of HIV-1 Nef with the AP-2 adaptor protein complex correlates with Nef-induced CD4 down-regulation. EMBO J 16:6964–6976 [CrossRef]
    [Google Scholar]
  12. Iafrate A. J., Bronson S., Skowronski J. 1997; Separable functions of Nef disrupt two aspects of T cell receptor machinery: CD4 expression and CD3 signaling. EMBO J 16:673–684 [CrossRef]
    [Google Scholar]
  13. Kasper M. R., Collins K. L. 2003; Nef-mediated disruption of HLA-A2 transport to the cell surface in T cells. J Virol 77:3041–3049 [CrossRef]
    [Google Scholar]
  14. Kestler H. W. III, Ringler D. J., Mori K., Panicali D. L., Sehgal P. K., Daniel M. D., Desrosiers R. C. 1991; Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell 65:651–662 [CrossRef]
    [Google Scholar]
  15. Kirchhoff F., Greenough T. C., Brettler D. B., Sullivan J. L., Desrosiers R. C. 1995; Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. N Engl J Med 332:228–232 [CrossRef]
    [Google Scholar]
  16. Lama J. 2003; The physiological relevance of CD4 receptor down-modulation during HIV infection. Curr HIV Res 1:167–184 [CrossRef]
    [Google Scholar]
  17. Moller B. K., Andresen B. S., Christensen E. I., Petersen C. M. 1990; Surface membrane CD4 turnover in phorbol ester stimulated T-lymphocytes. Evidence of degradation and increased synthesis. FEBS Lett 276:59–62 [CrossRef]
    [Google Scholar]
  18. Oldridge J., Marsh M. 1998; Nef—an adaptor adaptor?. Trends Cell Biol 8:302–305 [CrossRef]
    [Google Scholar]
  19. Pelchen-Matthews A., Armes J. E., Griffiths G., Marsh M. 1991; Differential endocytosis of CD4 in lymphocytic and nonlymphocytic cells. J Exp Med 173:575–587 [CrossRef]
    [Google Scholar]
  20. Preusser A., Briese L., Baur A. S., Willbold D. 2001; Direct in vitro binding of full-length human immunodeficiency virus type 1 Nef protein to CD4 cytoplasmic domain. J Virol 75:3960–3964 [CrossRef]
    [Google Scholar]
  21. Rose J. J., Janvier K., Chandrasekhar S., Sekaly R. P., Bonifacino J. S., Venkatesan S. 2005; CD4 down-regulation by HIV-1 and simian immunodeficiency virus (SIV) Nef proteins involves both internalization and intracellular retention mechanisms. J Biol Chem 280:7413–7426 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.83164-0
Loading
/content/journal/jgv/10.1099/vir.0.83164-0
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

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