VPU - Viral Protein U

HIV VPU acts in the degradation of CD4 in the endoplasmic reticulum and the enhancement of virion release from the plasma membrane.

PDB-1VPU: HIV-1 (isolate SF_162) Vpu cytoplasmic domain fragment (residues 39-81) with R37L and K38Q mutations - produced using SwissModel/SPDBV/POVray

Key web links:
ViralZone: HIV-1, HIV replication cycle, HIV resource
PDB: 1VPU (HIV-1 Vpu)
UniProt: P05919 (HIV-1 HXB2 Vpu)
Chime Tutorial:  not available
HIV-1/Human Protein Interaction DB: HIV-1 Vpu
Los Alamos HIV structure DB: not available
EMBL: K03455 [EMBL/GenBank/DDBJ]


  • p16 (81 amino acids)


  • Vpu plays a role in HIV-induced CD4 downregulation by mediating the proteasomal degradation of newly synthesized CD4.
  • Vpu binds to CD4 at the endoplasmic reticulum (ER) membrane and recruits the SCF β-TrCP E3 ubiquitin ligase complex by directly interacting with β-TrCP.
  • This ubiquitination event targets CD4 degradation by the cytosolic proteasome through a dislocation step of CD4 which is mediated by the p97-UFD1L-NPL4 complex .
  • Vpu promotes progeny virion release from infected cells by antagonizing the tethering effect of BST2/tetherin .
  • Vpu also induces downregulation of the coactivating NK cell receptor NK, T-cell, B-cell antigen (NTB-A), as well as the activating NK cell receptor PVR/CD155 .


  • Host cytoplasm
  • Host cell membrane
  • Virion

Additional Information:

  • Late timing of expression.
  • Vpu is unique to HIV-1/SIVcpz viruses.
  • The formation of Env-CD4 complexes interferes with virion assembly.
  • CD4 downregulation and increased virion release are genetically distinct; are related to different domains .

Vpu Function & Host-Virus Protein Interactions:[TOP]

Interactions highlighted in the image:

Potential interactions (not in the image):

  • Casein kinase II phosphorylation at positions Ser52 and Ser56.
  • Vpu binds a cellular protein UBP, which helps facilitate virus particle assembly and release.
  • There is either a direct interaction between Vpu and Gag, or an indirect interaction through UBP.
  • Vpu and AP1M1 interaction allows Vpu to hijack the AP-dependent trafficking pathways [see GUAVAh AP1M1 interaction profile].

Genomic Location & Protein Sequence: [TOP]

HIV-1 (HXB2):

          10         20         30         40         50         60         70         80
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[download in fasta format]

Length: 81 amino acids
Molecular Weight: 9111 Da
Theoretical pI: 4.69
Gene Description: Vpu translation initiation codon is not efficient .

Protein Domains/Folds/Motifs: [TOP]


VPU Protein - IPR008187

VPU Protein (C-terminal cytoplasmic domain) - IPR009032

  • is responsible for direct interaction with and degradation of the CD4 receptor.
  • encompasses the C-terminal half of the protein.
  • contains a few helical turns.
  • does not contain an apparent hydrophobic core.

Secondary Structure prediction:

Transmembrane Regions - tmhmm:

Low Complexity Regions - seg:

Antigenic Sites - EMBOSS:

Predicted Motifs: Printer-friendly version

Protein kinase C:
Casein kinase II:
Tyrosine kinase:
cAMP / cGMP kinase:
Cell attachment motif:
Asp Protease motif:
Asp Prot Retro motif:
Arginine-rich Region:
Isoleucine-rich Region:
Cysteine-rich Region:
Tryptophan-rich Region:
Zinc-finger CCHC motif:
Leucine Zipper motif:

Primary and Secondary Database Entries: [TOP]


ViralZone: HIV-1, HIV replication cycle, HIV resource
PDB/MMDB: Search for HIV-1 & VPU

UniProt: P05919 (HIV-1 HXB2 Vpu)
EMBL: K03455; CDS Not Annotated [EMBL/GenBank/DDBJ]

InterPro: IPR008187 Vpu / IPR009032 Vpu_cyt
Pfam: PF00558
Prints: none
SCOP: SSF57647 HIV-1 VPU cytoplasmic domain
BLOCKS: P05919
Prosite: P05919
ProtoNet: P05919
Database of Interacting Proteins: P05919
ModBase: P05919
HIV-1/Human Protein Interaction DB: HIV-1 Vpu
HIV-1 Sequence Database Los Alamos HIV Sequence Database


Reviews and References: [TOP]

1 - HIV Sequence Compendium 2000
Kuiken CL, Foley B, Hahn B, Korber B, Marx PA, McCutchan F, Mellors JW, Mullins JI, Sodroski J, Wolinksy S.
Theoretical Biol. & Biophys. Group, Los Alamos Nat Lab, LA-UR 01-3860 [Read it online: Compendium]
2 - Retroviruses
Coffin JM, Hughes SH, Varmus HE.
CD-ROM ed. (2002) Cold Spring Harbor Laboratory Press [Read it online: NCBI Bookshelf]
3 - Identification and localization of vpr gene product of human immunodeficiency virus type 1.
Sato A, Igarashi H, Adachi A.
Virus Genes 4: 303-312 (1990) [pubmed: 2149621]
4 - Env and Vpu proteins of human immunodeficiency virus type 1 are produced from multiple
bicistronic mRNAs.
Schwartz S, Felber BK, Fenyo EM, Pavlakis GN.
J Virol 64: 5448-5456 (1990) [pubmed: 2214021]
5 - The two biological activities of human immunodeficiency virus type 1 Vpu protein involve
two separable structural domains.
Schubert U, Bour S, Ferrer-Montiel AV.
J Virol 70: 809-819 (1996) [pubmed: 8551619]
6 - Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4.
Willey RL, Maldarelli F, Martin MA.
J Virol 66(12): 7193-7200 (1992) [pubmed: 1433512]
7 - The human immunodeficiency virus type 1-specific protein vpu is required for efficient virus
maturation and release.
Klimkait T, Strebel K, Hoggan MD.
J Virol 64: 621-629 (1990) [pubmed: 2404139]
8 - Modulation of HIV-1-host interaction: role of the Vpu accessory protein.
Dubé M, Bego MG, Paquay C, Cohen ÉA.
Retrovirology 7:114 (2010) [pubmed: 21176220]
9 - HIV-1 Vpu affects the anterograde transport and the glycosylation pattern of NTB-A.
Bolduan S, Hubel P, Reif T, Lodermeyer V, Höhne K, Fritz JV, Sauter D, Kirchhoff F, Fackler OT, Schindler M, Schubert U.
Virology 440(2):190-203 (2013) [pubmed: 23528733]
10 - HIV-1 Vpu mediated downregulation of CD155 requires alanine residues 10, 14 and 18 of the transmembrane domain.
Bolduan S, Reif T, Schindler M, Schubert U.
Virology 464-465:375-84 (2014) [pubmed: 25113908]
11 - Mapping the interaction between the cytoplasmic domains of HIV-1 viral protein U and human CD4 with NMR spectroscopy.
Singh SK, Möckel L, Thiagarajan-Rosenkranz P, Wittlich M, Willbold D, Koenig BW.
FEBS J. 279(19):3705-14 (2012) [pubmed: 22863293]
12 - A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway
through an F-box motif.
Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K, Benarous R.
Mol Cell 1(4):565-74 (1998) [pubmed: 9660940]
13 - HIV-1 Vpu protein antagonizes innate restriction factor BST-2 via lipid-embedded helix-helix interactions.
Skasko M, Wang Y, Tian Y, Tokarev A, Munguia J, Ruiz A, Stephens EB, Opella SJ, Guatelli J.
J Biol Chem. 287(1):58-67 (2012) [pubmed: 22072710]
14 - Structural basis of HIV-1 Vpu-mediated BST2 antagonism via hijacking of the clathrin adaptor protein complex 1.
Jia X, Weber E, Tokarev A, Lewinski M, Rizk M, Suarez M, Guatelli J, Xiong Y.
Elife 3:e02362 (2014) [pubmed: 24843023]

Thanks to ViralZone at the Swiss Institute of Bioinformatics (SIB) for allowing the use of their images on bioafrica.net.
Page last updated by Megan Druce, Paula Sommer and Tulio de Oliveira (UKZN/Africa Centre) & Philippe Le Mercier, Chantal Hulo and Patrick Masson (SIB/ViralZone).