1887

Abstract

Human immunodeficiency virus type 1 (HIV-1)-mediated CD4 downregulation is an important determinant of viral replication . Research on cellular co-factors involved in this process could lead to the identification of potential therapeutic targets. We found that CD4 surface levels were significantly higher in HIV-1-infected cells knocked-down for the HIV Rev-binding protein (HRB) compared with control cells. HRB knock-down affected CD4 downregulation induced by Nef but not by HIV-1 Vpu. Interestingly, the knock-down of the related protein HRBL (HRB-like), but not of the HRB interaction partner EPS15 (epidermal growth factor receptor pathway substrate 15), increased CD4 levels in Vpu-expressing cells significantly. Both of these proteins are known to be involved in HIV-1-mediated CD4 downregulation as co-factors of HIV-1 Nef. These results identify HRB as a previously unknown co-factor for HIV-1 Nef-mediated CD4 downregulation and highlight differences with the related protein HRBL, which affects the CD4 downregulation in a dual role as co-factor of both HIV-1 Nef and Vpu.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000382
2016-03-01
2019-10-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/97/3/778.html?itemId=/content/journal/jgv/10.1099/jgv.0.000382&mimeType=html&fmt=ahah

References

  1. Ali A. , Realegeno S. , Yang O. O. , Lewis M. J. . ( 2009;). Simultaneous assessment of CD4 and MHC-I downregulation by Nef primary isolates in the context of infection. J Virol Methods 161: 297–304 [CrossRef] [PubMed].
    [Google Scholar]
  2. Argañaraz E. R. , Schindler M. , Kirchhoff F. , Cortes M. J. , Lama J. . ( 2003;). Enhanced CD4 down-modulation by late stage HIV-1 nef alleles is associated with increased Env incorporation and viral replication. J Biol Chem 278: 33912–33919 [CrossRef] [PubMed].
    [Google Scholar]
  3. Arhel N. , Kirchhoff F. . ( 2010;). Host proteins involved in HIV infection: new therapeutic targets. Biochim Biophys Acta 1802: 313–321 [CrossRef] [PubMed].
    [Google Scholar]
  4. Binette J. , Dubé M. , Mercier J. , Halawani D. , Latterich M. , Cohen E. A. . ( 2007;). Requirements for the selective degradation of CD4 receptor molecules by the human immunodeficiency virus type 1 Vpu protein in the endoplasmic reticulum. Retrovirology 4: 75 [CrossRef] [PubMed].
    [Google Scholar]
  5. Bour S. , Boulerice F. , Wainberg M. A. . ( 1991;). Inhibition of gp160 and CD4 maturation in U937 cells after both defective and productive infections by human immunodeficiency virus type 1. J Virol 65: 6387–6396 [PubMed].
    [Google Scholar]
  6. Burtey A. , Rappoport J. Z. , Bouchet J. , Basmaciogullari S. , Guatelli J. , Simon S. M. , Benichou S. , Benmerah A. . ( 2007;). Dynamic interaction of HIV-1 Nef with the clathrin-mediated endocytic pathway at the plasma membrane. Traffic 8: 61–76 [CrossRef] [PubMed].
    [Google Scholar]
  7. Carl S. , Greenough T. C. , Krumbiegel M. , Greenberg M. , Skowronski J. , Sullivan J. L. , Kirchhoff F. . ( 2001;). Modulation of different human immunodeficiency virus type 1 Nef functions during progression to AIDS. J Virol 75: 3657–3665 [CrossRef] [PubMed].
    [Google Scholar]
  8. Casartelli N. , Di Matteo G. , Potestà M. , Rossi P. , Doria M. . ( 2003;). 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] [PubMed].
    [Google Scholar]
  9. Chaineau M. , Danglot L. , Proux-Gillardeaux V. , Galli T. . ( 2008;). Role of HRB in clathrin-dependent endocytosis. J Biol Chem 283: 34365–34373 [CrossRef] [PubMed].
    [Google Scholar]
  10. Chaudhuri R. , Lindwasser O. W. , Smith W. J. , Hurley J. H. , Bonifacino J. S. . ( 2007;). Downregulation of CD4 by human immunodeficiency virus type 1 Nef is dependent on clathrin and involves direct interaction of Nef with the AP2 clathrin adaptor. J Virol 81: 3877–3890 [CrossRef] [PubMed].
    [Google Scholar]
  11. daSilva L. L. , Sougrat R. , Burgos P. V. , Janvier K. , Mattera R. , Bonifacino J. S. . ( 2009;). Human immunodeficiency virus type 1 Nef protein targets CD4 to the multivesicular body pathway. J Virol 83: 6578–6590 [CrossRef] [PubMed].
    [Google Scholar]
  12. Doria M. , Salcini A. E. , Colombo E. , Parslow T. G. , Pelicci P. G. , Di Fiore P. P. . ( 1999;). The eps15 homology (EH) domain-based interaction between eps15 and hrb connects the molecular machinery of endocytosis to that of nucleocytosolic transport. J Cell Biol 147: 1379–1384 [CrossRef] [PubMed].
    [Google Scholar]
  13. Dubé M. , Bego M. G. , Paquay C. , Cohen E. A. . ( 2010;). Modulation of HIV-1–host interaction: role of the Vpu accessory protein. Retrovirology 7: 114 [CrossRef] [PubMed].
    [Google Scholar]
  14. Fritz C. C. , Zapp M. L. , Green M. R. . ( 1995;). A human nucleoporin-like protein that specifically interacts with HIV Rev. Nature 376: 530–533 [CrossRef] [PubMed].
    [Google Scholar]
  15. Jabbar M. A. , Nayak D. P. . ( 1990;). Intracellular interaction of human immunodeficiency virus type 1 (ARV-2) envelope glycoprotein gp160 with CD4 blocks the movement and maturation of CD4 to the plasma membrane. J Virol 64: 6297–6304 [PubMed].
    [Google Scholar]
  16. Jin Y.-J. , Cai C. Y. , Zhang X. , Zhang H. T. , Hirst J. A. , Burakoff S. J. . ( 2005;). HIV Nef-mediated CD4 down-regulation is adaptor protein complex 2 dependent. J Immunol 175: 3157–3164 [CrossRef] [PubMed].
    [Google Scholar]
  17. Kutsch O. , Benveniste E. N. , Shaw G. M. , Levy D. N. . ( 2002;). Direct and quantitative single-cell analysis of human immunodeficiency virus type 1 reactivation from latency. J Virol 76: 8776–8786 [CrossRef] [PubMed].
    [Google Scholar]
  18. Landi A. , Iannucci V. , Nuffel A. V. , Meuwissen P. , Verhasselt B. . ( 2011;). One protein to rule them all: modulation of cell surface receptors and molecules by HIV Nef. Curr HIV Res 9: 496–504 [CrossRef] [PubMed].
    [Google Scholar]
  19. Landi A. , Vermeire J. , Iannucci V. , Vanderstraeten H. , Naessens E. , Bentahir M. , Verhasselt B. . ( 2014;). Genome-wide shRNA screening identifies host factors involved in early endocytic events for HIV-1-induced CD4 down-regulation. Retrovirology 11: 118 [CrossRef] [PubMed].
    [Google Scholar]
  20. Levy D. N. , Aldrovandi G. M. , Kutsch O. , Shaw G. M. . ( 2004;). Dynamics of HIV-1 recombination in its natural target cells. Proc Natl Acad Sci U S A 101: 4204–4209 [CrossRef] [PubMed].
    [Google Scholar]
  21. Magadán J. G. , Pérez-Victoria F. J. , Sougrat R. , Ye Y. , Strebel K. , Bonifacino J. S. . ( 2010;). Multilayered mechanism of CD4 downregulation by HIV-1 Vpu involving distinct ER retention and ERAD targeting steps. PLoS Pathog 6: e1000869 [CrossRef] [PubMed].
    [Google Scholar]
  22. Mann J. K. , Byakwaga H. , Kuang X. T. , Le A. Q. , Brumme C. J. , Mwimanzi P. , Omarjee S. , Martin E. , Lee G. Q. , other authors . ( 2013;). Ability of HIV-1 Nef to downregulate CD4 and HLA class I differs among viral subtypes. Retrovirology 10: 100 [CrossRef] [PubMed].
    [Google Scholar]
  23. Mann J. K. , Chopera D. , Omarjee S. , Kuang X. T. , Le A. Q. , Anmole G. , Danroth R. , Mwimanzi P. , Reddy T. , other authors . ( 2014;). Nef-mediated down-regulation of CD4 and HLA class I in HIV-1 subtype C infection: association with disease progression and influence of immune pressure. Virology 468–470: 214–225 [CrossRef] [PubMed].
    [Google Scholar]
  24. 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 [CrossRef] [PubMed].
    [Google Scholar]
  25. Pryor P. R. , Jackson L. , Gray S. R. , Edeling M. A. , Thompson A. , Sanderson C. M. , Evans P. R. , Owen D. J. , Luzio J. P. . ( 2008;). Molecular basis for the sorting of the SNARE VAMP7 into endocytic clathrin-coated vesicles by the ArfGAP Hrb. Cell 134: 817–827 [CrossRef] [PubMed].
    [Google Scholar]
  26. Salcini A. E. , Confalonieri S. , Doria M. , Santolini E. , Tassi E. , Minenkova O. , Cesareni G. , Pelicci P. G. , Di Fiore P. P. . ( 1997;). Binding specificity and in vivo targets of the EH domain, a novel protein-protein interaction module. Genes Dev 11: 2239–2249 [CrossRef] [PubMed].
    [Google Scholar]
  27. Schaefer M. R. , Wonderlich E. R. , Roeth J. F. , Leonard J. A. , Collins K. L. . ( 2008;). HIV-1 Nef targets MHC-I and CD4 for degradation via a final common beta-COP-dependent pathway in T cells. PLoS Pathog 4: e1000131 [CrossRef] [PubMed].
    [Google Scholar]
  28. Stove V. , Naessens E. , Stove C. , Swigut T. , Plum J. , Verhasselt B. . ( 2003;). Signaling but not trafficking function of HIV-1 protein Nef is essential for Nef-induced defects in human intrathymic T-cell development. Blood 102: 2925–2932 [CrossRef] [PubMed].
    [Google Scholar]
  29. Stove V. , Van de Walle I. , Naessens E. , Coene E. , Stove C. , Plum J. , Verhasselt B. . ( 2005;). Human immunodeficiency virus Nef induces rapid internalization of the T-cell coreceptor CD8alphabeta. J Virol 79: 11422–11433 [CrossRef] [PubMed].
    [Google Scholar]
  30. Tintori C. , Brai A. , Fallacara A. L. , Fazi R. , Schenone S. , Botta M. . ( 2014;). Protein–protein interactions and human cellular cofactors as new targets for HIV therapy. Curr Opin Pharmacol 18: 1–8 [CrossRef] [PubMed].
    [Google Scholar]
  31. van Bergen en Henegouwen P. M. P. . ( 2009;). EPS15: a multifunctional adaptor protein regulating intracellular trafficking. Cell Communication and Signalling 7: 24.[CrossRef]
    [Google Scholar]
  32. Vandesompele J. , De Preter K. , Pattyn F. , Poppe B. , Van Roy N. , De Paepe A. , Speleman F. . ( 2002;). Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3: RESEARCH0034.[CrossRef]
    [Google Scholar]
  33. Verhasselt B. , Naessens E. , Verhofstede C. , De Smedt M. , Schollen S. , Kerre T. , Vanhecke D. , Plum J. . ( 1999;). Human immunodeficiency virus nef gene expression affects generation and function of human T cells, but not dendritic cells. Blood 94: 2809–2818 [PubMed].
    [Google Scholar]
  34. Vermeire J. , Naessens E. , Vanderstraeten H. , Landi A. , Iannucci V. , Van Nuffel A. , Taghon T. , Pizzato M. , Verhasselt B. . ( 2012;). Quantification of reverse transcriptase activity by real-time PCR as a fast and accurate method for titration of HIV, lenti- and retroviral vectors. PLoS One 7: e50859 [CrossRef] [PubMed].
    [Google Scholar]
  35. Watkins R. L. , Zou W. , Denton P. W. , Krisko J. F. , Foster J. L. , Garcia J. V. . ( 2013;). In vivo analysis of highly conserved Nef activities in HIV-1 replication and pathogenesis. Retrovirology 10: 125 [CrossRef] [PubMed].
    [Google Scholar]
  36. Wildum S. , Schindler M. , Münch J. , Kirchhoff F. . ( 2006;). Contribution of Vpu, Env, and Nef to CD4 down-modulation and resistance of human immunodeficiency virus type 1-infected T cells to superinfection. J Virol 80: 8047–8059 [CrossRef] [PubMed].
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000382
Loading
/content/journal/jgv/10.1099/jgv.0.000382
Loading

Data & Media loading...

Supplements

Supplementary Data



PDF

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