1887

Journal of General Virology header logo

Volume 97, Issue 3

The human immunodeficiency virus (HIV) Rev-binding protein (HRB) is a co-factor for HIV-1 Nef-mediated CD4 downregulation Free

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.

  • Received:
  • Accepted:
  • Published Online:
© 2016 The Authors
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000382
2016-03-01
2024-04-25
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 [View Article][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 [View Article][PubMed]
     [Google Scholar]
  3. Arhel N., Kirchhoff F. 2010; Host proteins involved in HIV infection: new therapeutic targets. Biochim Biophys Acta 1802:313–321 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000382
Loading
The human immunodeficiency virus (HIV) Rev-binding protein (HRB) is a co-factor for HIV-1 Nef-mediated CD4 downregulation
J. Gen. Virol. 97, 778 (2016); https://doi.org/10.1099/jgv.0.000382
/content/journal/jgv/10.1099/jgv.0.000382
/content/journal/jgv/10.1099/jgv.0.000382
Loading

Data & Media loading...

Supplements

Supplementary Data

PDF

Most cited 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