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PMID: 19264781 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The human immunodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1 DCAF1 ubiquitin ligase to overcome a postentry block in macrophage infection.

Journal of virology ·Vol. 83 ·No. 10 ·2009-05-00 ·Pages 4854-60

Bergamaschi A, Ayinde D, David A, Le Rouzic E, Morel M, Collin G, Descamps D, Damond F, Brun-Vezinet F, Nisole S, Margottin-Goguet F, Pancino G, Transy C

Abstract

The human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) genomes encode several auxiliary proteins that have increasingly shown their importance in the virus-host relationship. One of these proteins, Vpx, is unique to the HIV-2/SIVsm lineage and is critical for viral replication in macrophages. The functional basis for this requirement, as well as the Vpx mode of action, has remained unexplained, and it is all the more enigmatic that HIV type 1 (HIV-1), which has no Vpx counterpart, can infect macrophages. Here, we underscore DCAF1 as a critical host effector of Vpx in its ability to mediate infection and long-term replication of HIV-2 in human macrophages. Vpx assembles with the CUL4A-DDB1 ubiquitin ligase through DCAF1 recruitment. Precluding Vpx present in the incoming virions from recruiting DCAF1 in target macrophages leads to a postentry block characterized by defective accumulation of HIV-2 reverse transcripts. In addition, Vpx from SIVsm functionally complements Vpx-defective HIV-2 in a DCAF1-binding-dependent manner. Altogether, our data point to a mechanism in which Vpx diverts the Cul4A-DDB1(DCAF1) ligase to inactivate an evolutionarily conserved factor, which restricts macrophage infection by HIV-2 and closely related simian viruses.

MeSH Terms
CD4-Positive T-Lymphocytes/virology Cullin Proteins/metabolism DNA-Binding Proteins/metabolism Gene Knockdown Techniques Gene Silencing HIV Infections/virology HIV-2/genetics,metabolism,physiology HeLa Cells Humans Macrophages/virology Simian Immunodeficiency Virus/metabolism,physiology Ubiquitin-Protein Ligases/metabolism Viral Regulatory and Accessory Proteins/metabolism Virus Replication
Chemicals
CUL4A protein, human Cullin Proteins DDB1 protein, human DNA-Binding Proteins VPX protein, Human immunodeficiency virus 2 Viral Regulatory and Accessory Proteins Ubiquitin-Protein Ligases
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Bergamaschi Anna
Institut Pasteur, Unité de Régulation des Infections Rétrovirales, 25 rue du Dr Roux, 75724 Paris Cedex 15, France.
Ayinde Diana
David Annie
Le Rouzic Erwann
Morel Marina
Collin Gilles
Descamps Diane
Damond Florence
Brun-Vezinet Françoise
Nisole Sebastien
Margottin-Goguet Florence
Pancino Gianfranco
Transy Catherine
References (49)
49 references, click to expand
  1. UVDDB p127-binding modulates activities and intracellular distribution of hepatitis B virus X protein.
    Oncogene. 2000 Sep 7;19(38):4417-26 PMID: 10980617
  2. The engagement of activating FcgammaRs inhibits primate lentivirus replication in human macrophages.
    J Immunol. 2006 Nov 1;177(9):6291-300 PMID: 17056559
  3. Uracil DNA glycosylase specifically interacts with Vpr of both human immunodeficiency virus type 1 and simian immunodeficiency virus of sooty mangabeys, but binding does not correlate with cell cycle arrest.
    J Virol. 1997 Jun;71(6):4842-6 PMID: 9151883
  4. Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity.
    J Virol. 1995 Nov;69(11):6705-11 PMID: 7474080
  5. AIDS as a zoonosis: scientific and public health implications.
    Science. 2000 Jan 28;287(5453):607-14 PMID: 10649986
  6. DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase.
    Mol Cell. 2007 Jun 22;26(6):775-80 PMID: 17588513
  7. Interaction with the p6 domain of the gag precursor mediates incorporation into virions of Vpr and Vpx proteins from primate lentiviruses.
    J Virol. 1999 Jan;73(1):592-600 PMID: 9847364
  8. Nuclear import and cell cycle arrest functions of the HIV-1 Vpr protein are encoded by two separate genes in HIV-2/SIV(SM).
    EMBO J. 1996 Nov 15;15(22):6155-65 PMID: 8947037
  9. HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase.
    Cell Cycle. 2007 Jan 15;6(2):182-8 PMID: 17314515
  10. Human immunodeficiency virus type 1 spinoculation enhances infection through virus binding.
    J Virol. 2000 Nov;74(21):10074-80 PMID: 11024136
  11. The C-terminal proline-rich tail of human immunodeficiency virus type 2 Vpx is necessary for nuclear localization of the viral preintegration complex in nondividing cells.
    J Virol. 2000 Jul;74(13):6162-7 PMID: 10846100
  12. Unique features of TRIM5alpha among closely related human TRIM family members.
    Virology. 2007 Apr 10;360(2):419-33 PMID: 17156811
  13. SIVSM/HIV-2 Vpx proteins promote retroviral escape from a proteasome-dependent restriction pathway present in human dendritic cells.
    Retrovirology. 2007 Jan 09;4:2 PMID: 17212817
  14. DDB1 and Cul4A are required for human immunodeficiency virus type 1 Vpr-induced G2 arrest.
    J Virol. 2007 Oct;81(19):10822-30 PMID: 17626091
  15. Out of Africa: what can we learn from HIV-2 about protective immunity to HIV-1?
    Nat Immunol. 2007 Apr;8(4):329-31 PMID: 17375091
  16. Elimination of HIV-1 plasmid DNA from virus samples obtained from transfection by calcium-phosphate co-precipitation.
    J Virol Methods. 2000 Oct;90(1):99-102 PMID: 11011086
  17. Functional analysis of the simian immunodeficiency virus Vpx protein: identification of packaging determinants and a novel nuclear targeting domain.
    J Virol. 2001 Jan;75(1):362-74 PMID: 11119605
  18. The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection.
    J Virol. 1995 Feb;69(2):882-8 PMID: 7815556
  19. Positive selection of primate TRIM5alpha identifies a critical species-specific retroviral restriction domain.
    Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2832-7 PMID: 15689398
  20. Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes.
    Virology. 1995 Feb 1;206(2):935-44 PMID: 7531918
  21. Human immunodeficiency virus Vpx is required for the early phase of replication in peripheral blood mononuclear cells.
    Microbiol Immunol. 1994;38(11):871-8 PMID: 7898386
  22. Isolation of a new human retrovirus from West African patients with AIDS.
    Science. 1986 Jul 18;233(4761):343-6 PMID: 2425430
  23. Identification of host proteins required for HIV infection through a functional genomic screen.
    Science. 2008 Feb 15;319(5865):921-6 PMID: 18187620
  24. VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation.
    Oncogene. 2008 Jul 3;27(29):4056-64 PMID: 18332868
  25. Vpx is required for dissemination and pathogenesis of SIV(SM) PBj: evidence of macrophage-dependent viral amplification.
    Nat Med. 1998 Dec;4(12):1401-8 PMID: 9846578
  26. The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells.
    Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7311-5 PMID: 8041786
  27. Human immunodeficiency virus type 2 vpx protein augments viral infectivity.
    Virology. 1991 Sep;184(1):197-209 PMID: 1714662
  28. Antibodies to several conformation-dependent epitopes of gp120/gp41 inhibit CCR-5-dependent cell-to-cell fusion mediated by the native envelope glycoprotein of a primary macrophage-tropic HIV-1 isolate.
    Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9326-31 PMID: 9256481
  29. Vpx is critical for reverse transcription of the human immunodeficiency virus type 2 genome in macrophages.
    J Virol. 2008 Aug;82(15):7752-6 PMID: 18495778
  30. The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2 + M phase of the cell cycle.
    J Virol. 1995 Oct;69(10):6304-13 PMID: 7666531
  31. Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle.
    Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11778-83 PMID: 17609381
  32. Characterization of simian immunodeficiency virus SIVSM/human immunodeficiency virus type 2 Vpx function in human myeloid cells.
    J Virol. 2008 Dec;82(24):12335-45 PMID: 18829761
  33. VPX mutants of HIV-2 are infectious in established cell lines but display a severe defect in peripheral blood lymphocytes.
    EMBO J. 1989 Apr;8(4):1169-75 PMID: 2743977
  34. Analysis of the function of viral protein X (VPX) of HIV-2.
    Virology. 1989 Dec;173(2):624-30 PMID: 2596032
  35. HIV-1 Vpr activates the G2 checkpoint through manipulation of the ubiquitin proteasome system.
    Virol J. 2007 Jun 08;4:57 PMID: 17559673
  36. The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys.
    Nature. 2004 Feb 26;427(6977):848-53 PMID: 14985764
  37. Assembly with the Cul4A-DDB1DCAF1 ubiquitin ligase protects HIV-1 Vpr from proteasomal degradation.
    J Biol Chem. 2008 Aug 1;283(31):21686-92 PMID: 18524771
  38. A conserved dileucine-containing motif in p6(gag) governs the particle association of Vpx and Vpr of simian immunodeficiency viruses SIV(mac) and SIV(agm).
    J Virol. 1999 Dec;73(12):9992-9 PMID: 10559313
  39. Functional analysis of the vpx, vpr, and nef genes of simian immunodeficiency virus.
    J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Apr 1;8(4):335-44 PMID: 7882097
  40. HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding protein DDB1.
    Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4130-5 PMID: 17360488
  41. Vpr-induced cell cycle arrest is conserved among primate lentiviruses.
    J Virol. 1996 Apr;70(4):2516-24 PMID: 8642681
  42. Conservation and host specificity of Vpr-mediated cell cycle arrest suggest a fundamental role in primate lentivirus evolution and biology.
    J Virol. 1997 Jun;71(6):4331-8 PMID: 9151821
  43. Primate lentiviral Vpx commandeers DDB1 to counteract a macrophage restriction.
    PLoS Pathog. 2008 May 02;4(5):e1000057 PMID: 18451984
  44. Lentiviral Vpx accessory factor targets VprBP/DCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligase to enable macrophage infection.
    PLoS Pathog. 2008 May 09;4(5):e1000059 PMID: 18464893
  45. Vpx and Vpr proteins of HIV-2 up-regulate the viral infectivity by a distinct mechanism in lymphocytic cells.
    Microbes Infect. 2003 Apr;5(5):387-95 PMID: 12737994
  46. Evolution of the primate lentiviruses: evidence from vpx and vpr.
    EMBO J. 1992 Sep;11(9):3405-12 PMID: 1324171
  47. HIV-1 Vpr-mediated G2 arrest involves the DDB1-CUL4AVPRBP E3 ubiquitin ligase.
    PLoS Pathog. 2007 Jul;3(7):e85 PMID: 17630831
  48. Distinct effects in primary macrophages and lymphocytes of the human immunodeficiency virus type 1 accessory genes vpr, vpu, and nef: mutational analysis of a primary HIV-1 isolate.
    Virology. 1994 May 1;200(2):623-31 PMID: 8178448
  49. Human immunodeficiency virus type 1 Vpr arrests the cell cycle in G2 by inhibiting the activation of p34cdc2-cyclin B.
    J Virol. 1995 Nov;69(11):6859-64 PMID: 7474100
Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
1098-5514
DOI
10.1128/JVI.00187-09
Published
2009-05-00
Epub
2009-00-04
Pages
4854-60
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC2682070
Subset
IM
External Links
PubMed source DOI: 10.1128/JVI.00187-09 PMC Full Text View journal details
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