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Protein Nef



Human immunodeficiency virus type 1 group M subtype B (isolate LW123) (HIV-1)
Reviewed-Annotation score: -Experimental evidence at protein leveli


Factor of infectivity and pathogenicity, required for optimal virus replication. Alters numerous pathways of T-lymphocytes function and down-regulates immunity surface molecules in order to evade host defense and increase viral infectivity. Alters the functionality of other immunity cells, like dendritic cells, monocytes/macrophages and NK cells.UniRule annotation
In infected CD4+ T-lymphocytes, down-regulates the surface MHC-I, mature MHC-II, CD4, CD28, CCR5 and CXCR4 molecules. Mediates internalization and degradation of host CD4 through the interaction of with the cytoplasmic tail of CD4, the recruitment of AP-2 (clathrin adapter protein complex 2), internalization through clathrin coated pits, and subsequent transport to endosomes and lysosomes for degradation. Diverts host MHC-I molecules to the trans-Golgi network-associated endosomal compartments by an endocytic pathway to finally target them for degradation. MHC-I down-regulation may involve AP-1 (clathrin adapter protein complex 1) or possibly Src family kinase-ZAP70/Syk-PI3K cascade recruited by PACS2. In consequence infected cells are masked for immune recognition by cytotoxic T-lymphocytes. Decreasing the number of immune receptors also prevents reinfection by more HIV particles (superinfection). Down-regulates host SERINC3 and SERINC5 thereby excluding these proteins from the viral particles. Virion infectivity is drastically higher when SERINC3 or SERINC5 are excluded from the viral envelope, because these host antiviral proteins impare the membrane fusion event necessary for subsequent virion penetration.UniRule annotation
Bypasses host T-cell signaling by inducing a transcriptional program nearly identical to that of anti-CD3 cell activation. Interaction with TCR-zeta chain up-regulates the Fas ligand (FasL). Increasing surface FasL molecules and decreasing surface MHC-I molecules on infected CD4+ cells send attacking cytotoxic CD8+ T-lymphocytes into apoptosis.UniRule annotation
Plays a role in optimizing the host cell environment for viral replication without causing cell death by apoptosis. Protects the infected cells from apoptosis in order to keep them alive until the next virus generation is ready to strike. Inhibits the Fas and TNFR-mediated death signals by blocking MAP3K5/ASK1. Decreases the half-life of TP53, protecting the infected cell against p53-mediated apoptosis. Inhibits the apoptotic signals regulated by the Bcl-2 family proteins through the formation of a Nef/PI3-kinase/PAK2 complex that leads to activation of PAK2 and induces phosphorylation of host BAD.UniRule annotation
Extracellular Nef protein targets CD4+ T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors.UniRule annotation


HIV-1 lineages are divided in three main groups, M (for Major), O (for Outlier), and N (for New, or Non-M, Non-O). The vast majority of strains found worldwide belong to the group M. Group O seems to be endemic to and largely confined to Cameroon and neighboring countries in West Central Africa, where these viruses represent a small minority of HIV-1 strains. The group N is represented by a limited number of isolates from Cameroonian persons. The group M is further subdivided in 9 clades or subtypes (A to D, F to H, J and K).UniRule annotation


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei20Might play a role in AP-1 recruitment to the Nef-MHC-I complexUniRule annotation1

GO - Molecular functioni

GO - Biological processi


Biological processApoptosis, Host-virus interaction, Inhibition of host adaptive immune response by virus, Inhibition of host autophagy by virus, Inhibition of host MHC class I molecule presentation by virus, Inhibition of host MHC class II molecule presentation by virus, Viral immunoevasion, Virulence

Names & Taxonomyi

Protein namesi
Recommended name:
Protein NefUniRule annotation
Alternative name(s):
3'ORFUniRule annotation
Negative factorUniRule annotation
Short name:
F-proteinUniRule annotation
Cleaved into the following chain:
C-terminal core proteinUniRule annotation
Gene namesi
Name:nefUniRule annotation
OrganismiHuman immunodeficiency virus type 1 group M subtype B (isolate LW123) (HIV-1)
Taxonomic identifieri82834 [NCBI]
Taxonomic lineageiVirusesRetro-transcribing virusesRetroviridaeOrthoretrovirinaeLentivirusPrimate lentivirus group
Virus hostiHomo sapiens (Human) [TaxID: 9606]

Subcellular locationi

  • Host cell membrane UniRule annotation; Lipid-anchor UniRule annotation; Cytoplasmic side UniRule annotation
  • Virion UniRule annotation
  • Secreted UniRule annotation
  • Host Golgi apparatus membrane UniRule annotation
  • Note: TGN localization requires PACS1. Associates with the inner plasma membrane through its N-terminal domain. Nef stimulates its own export via the release of exosomes. Incorporated in virions at a rate of about 10 molecules per virion, where it is cleaved.UniRule annotation

GO - Cellular componenti

Keywords - Cellular componenti

Host cell membrane, Host Golgi apparatus, Host membrane, Membrane, Secreted, Virion

Pathology & Biotechi

Keywords - Diseasei


PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemoved; by hostUniRule annotation
ChainiPRO_00000383252 – 206Protein NefUniRule annotationAdd BLAST205
ChainiPRO_000003832658 – 206C-terminal core proteinUniRule annotationAdd BLAST149

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Lipidationi2N-myristoyl glycine; by hostUniRule annotation1
Modified residuei6Phosphoserine; by hostUniRule annotation1

Post-translational modificationi

The virion-associated Nef proteins are cleaved by the viral protease to release the soluble C-terminal core protein. Nef is probably cleaved concomitantly with viral structural proteins on maturation of virus particles.UniRule annotation
Myristoylated.UniRule annotation
Phosphorylated on serine residues, probably by host PKCdelta and theta.UniRule annotation


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei57 – 58Cleavage; by viral proteaseUniRule annotation2

Keywords - PTMi

Lipoprotein, Myristate, Phosphoprotein



Expressed early in the viral replication cycle.UniRule annotation

Keywords - Developmental stagei

Early protein


Subunit structurei

Monomer; cytosolic form. Homodimer; membrane bound form. Interacts with Nef associated p21-activated kinase (PAK2); this interaction activates PAK2. Associates with the Nef-MHC-I-AP1 complex; this complex is required for MHC-I internalization. Interacts (via C-terminus) with host PI3-kinase. Interacts with host PACS1; this interaction seems to be weak. Interacts with host PACS2. Interacts with host LCK and MAPK3; these interactions inhibit the kinase activity of the latters. Interacts with host ATP6V1H; this interaction may play a role in CD4 endocytosis. Associates with the CD4-Nef-AP2 complex; this complex is required for CD4 internalization. Interacts with host AP2 subunit alpha and AP2 subunit sigma2. Interacts with TCR-zeta chain; this interaction up-regulates the Fas ligand (FasL) surface expression. Interacts with host HCK, LYN, and SRC; these interactions activate the Src family kinases. Interacts with MAP3K5; this interaction inhibits the Fas and TNFR-mediated death signals. Interacts with beta-COP and PTE1. Interacts with human RACK1; this increases Nef phosphorylation by PKC. Interacts with TP53; this interaction decreases the half-life of TP53, protecting the infected cell against p53-mediated apoptosis.UniRule annotation

GO - Molecular functioni


Secondary structure

Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi81 – 93Combined sources13
Helixi106 – 115Combined sources10
Turni116 – 118Combined sources3
Beta strandi122 – 124Combined sources3
Beta strandi129 – 134Combined sources6
Beta strandi136 – 140Combined sources5
Beta strandi143 – 146Combined sources4
Beta strandi181 – 185Combined sources5
Helixi187 – 190Combined sources4
Helixi194 – 198Combined sources5
Helixi200 – 202Combined sources3

3D structure databases

Select the link destinations:
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum

Miscellaneous databases


Family & Domainsi


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni62 – 65Acidic; interacts with host PACS1 and PACS2; stabilizes the interaction of NEF/MHC-I with host AP1M1; necessary for MHC-I internalizationUniRule annotation4
Regioni69 – 78SH3-binding; interaction with Src family tyrosine kinasesUniRule annotation10
Regioni108 – 124Mediates dimerization, Nef-PTE1 interactionUniRule annotationAdd BLAST17
Regioni148 – 180Binding to ATP6V1HUniRule annotationAdd BLAST33


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi72 – 75PxxP; stabilizes the interaction of NEF/MHC-I with host AP1M1; necessary for MHC-I internalizationUniRule annotation4
Motifi164 – 165Dileucine internalization motif; necessary for CD4 internalizationUniRule annotation2
Motifi174 – 175Diacidic; necessary for CD4 internalizationUniRule annotation2


The N-terminal domain is composed of the N-myristoyl glycine and of a cluster of positively charged amino acids. It is required for inner plasma membrane targeting of Nef and virion incorporation, and thereby for infectivity. This domain is also involved in binding to TP53.UniRule annotation
The SH3-binding domain constituted of PxxP motifs mediates binding to several Src family proteins thereby regulating their tyrosine kinase activity. The same motifs also mediates the association with MAPK3, PI3-kinase and TCR-zeta.UniRule annotation
The dileucine internalization motif and a diacidic motif seem to be required for binding to AP-2.UniRule annotation
The acidic region binds to the sorting protein PACS-2, which targets Nef to the paranuclear region, enabling the PxxP motif to direct assembly of an SFK/ZAP-70/PI3K complex that accelerates endocytosis of cell-surface MHC-I.UniRule annotation

Sequence similaritiesi

Belongs to the lentivirus primate group Nef protein family.UniRule annotation

Keywords - Domaini


Family and domain databases

Gene3Di3.30.62.10, 1 hit
4.10.890.10, 1 hit
HAMAPiMF_04078 NEF_HIV, 1 hit
InterProiView protein in InterPro
IPR027480 HIV-1_Nef_anchor_sf
IPR027481 HIV-1_Nef_core_sf
IPR001558 HIV_Nef
PfamiView protein in Pfam
PF00469 F-protein, 1 hit
SUPFAMiSSF55671 SSF55671, 1 hit


Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q70627-1 [UniParc]FASTAAdd to basket

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Mass (Da):23,414
Last modified:January 23, 2007 - v3

Sequence databases

Select the link destinations:
Links Updated
U12055 Genomic RNA Translation: AAA76691.1

Similar proteinsi

Entry informationi

Entry nameiNEF_HV1LW
AccessioniPrimary (citable) accession number: Q70627
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: January 23, 2007
Last modified: May 23, 2018
This is version 123 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programViral Protein Annotation Program


Keywords - Technical termi

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