P12504 (VIF_HV1N5) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Virion infectivity factor
Short name=Vif

Alternative name(s):
SOR protein

Cleaved into the following 2 chains:

1. Virion infectivity factor p17
2. Virion infectivity factor p7

Gene names

Name:

vif

Organism

Human immunodeficiency virus type 1 group M subtype B (isolate NY5) (HIV-1)

Taxonomic identifier

11698 [NCBI]

Taxonomic lineage

Viruses › Retro-transcribing viruses › Retroviridae › Orthoretrovirinae › Lentivirus › Primate lentivirus group › Human immunodeficiency virus 1 › HIV-1 unknown group

Virus host

Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	192 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Counteracts the innate antiviral activity of human APOBEC3F and APOBEC3G. Forms a complex with host APOBEC3F and APOBEC3G thus preventing the entry of these lethally hypermutating enzymes into progeny virions. Recruits an active E3 ubiquitin ligase complex composed of elongin BC, CUL5, and RBX2 to induce polyubiquitination of APOBEC3G and APOBEC3F. In turn, they are directed to the 26S proteasome for degradation. Vif interaction with APOBEC3G also blocks its cytidine deaminase activity in a proteasome-independent manner, suggesting a dual inhibitory mechanism. May interact directly with APOBEC3G mRNA in order to inhibit its translation. Seems to play a role in viral morphology by affecting the stability of the viral nucleoprotein core. Finally, Vif also contributes to the G2 cell cycle arrest observed in HIV infected cells By similarity. Ref.4 Ref.10
Subunit structure	Homomultimer; in vitro and presumably in vivo. Interacts with viral RNA and Pr55Gag precursor; these interactions mediate Vif incorporation into the virion. Interacts with the viral reverse transcriptase. Interacts with human APOBEC3F and APOBEC3G. Interacts with host UBCE7IP1 isoform 3/ZIN and possibly with SAT. Interacts with host tyrosine kinases HCK and FYN; these interactions may decrease level of phosphorylated APOBEC3G incorporation into virions. Interacts with host ABCE1; this interaction may play a role in protecting viral RNA from damage during viral assembly. Forms an E3 ligase complex by interacting with human CUL5 and elongin BC complex (TCEB1 and TCEB2). Interacts with host MDM2; this interaction targets Vif for degradation by the proteasome By similarity. Ref.6 Ref.7 Ref.8 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16
Subcellular location	Host cytoplasm. Host cell membrane; Peripheral membrane protein; Cytoplasmic side. Virion. Note: Seems to colocalize with intermediate filament vimentin. A fraction is associated with the cytoplasmic side of cellular membranes, presumably via the interaction with Pr55Gag precursor. Incorporated in virions at a ratio of approximately 7 to 20 molecules per virion.
Induction	Expressed late during infection in a Rev-dependent manner. Ref.3
Domain	The BC-like-box motif mediates the interaction with elongin BC complex. The HCCH motif (H-x(5)-C-x(18)-C-x(5)-H) mediates the interaction with CUL5.
Post-translational modification	Processed in virion by the viral protease. Highly phosphorylated on serines and threonines residues. Thr-96 and Ser-165 are phosphorylated by the mitogen activated kinase MAP4K1. As the HIV-1 replication can be activated by stress and mitogens, these phosphorylations could be involved in this process. Ser-144 phosphorylation may inhibit elongin BC complex binding. Polyubiquitinated and degraded by the proteasome in the presence of APOBEC3G By similarity.
Miscellaneous	Required for replication in 'nonpermissive' cells, including primary T-cells, macrophages and certain T-cell lines, but is dispensable for replication in 'permissive' cell lines, such as 293T cells. In nonpermissive cells, Vif-defective viruses can produce virions, but they fail to complete reverse transcription and cannot successfully infect new cells. Vif-defective viruses show catastrophic failure in reverse transcription due to APOBEC-induced mutations that initiate a DNA base repair pathway and compromise the structural integrity of the ssDNA. In the absence of Vif, the virion is morphologically abnormal. The infectious clone pNL4-3 is a chimeric provirus that consists of DNA from HIV isolates NY5 (5' half) and BRU (3' half). 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).
Sequence similarities	Belongs to the primate lentivirus group Vif protein family.

Ontologies

Keywords
Biological process	Host-virus interaction Ubl conjugation pathway
Cellular component	Host cell membrane Host cytoplasm Host membrane Membrane Virion
Disease	AIDS
Ligand	RNA-binding
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological_process	RNA-dependent DNA replication Traceable author statement. Source: Reactome entry into host cell Traceable author statement. Source: Reactome uncoating of virus Traceable author statement. Source: Reactome viral infectious cycle Inferred from electronic annotation. Source: InterPro virus-host interaction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytosol Traceable author statement. Source: Reactome host cell cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell host cell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell membrane Inferred from electronic annotation. Source: UniProtKB-KW nucleoplasm Traceable author statement. Source: Reactome virion Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	RNA binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
AMBRA1	Q9C0C7	5	EBI-779991,EBI-2512975	From a different organism.
CBFB	Q13951	5	EBI-779991,EBI-718750	From a different organism.
CUL2	Q13617	5	EBI-779991,EBI-456179	From a different organism.
CUL5	Q93034	5	EBI-779991,EBI-1057139	From a different organism.
DCAF11	Q8TEB1	3	EBI-779991,EBI-2213388	From a different organism.
DNAJC7	Q99615	3	EBI-779991,EBI-357552	From a different organism.
GPS2	Q13227	2	EBI-779991,EBI-713355	From a different organism.
HCK	P08631	3	EBI-779991,EBI-346340	From a different organism.
HDAC3	O15379	2	EBI-779991,EBI-607682	From a different organism.
MAPK6	Q16659	2	EBI-779991,EBI-1384105	From a different organism.
PSME3	P61289	2	EBI-779991,EBI-355546	From a different organism.
RNF216	Q9NWF9-3	4	EBI-779991,EBI-723337	From a different organism.
RNF7	Q9UBF6	4	EBI-779991,EBI-398632	From a different organism.
SQSTM1	Q13501	2	EBI-779991,EBI-307104	From a different organism.
STUB1	Q9UNE7	2	EBI-779991,EBI-357085	From a different organism.
TCEB1	Q15369	5	EBI-779991,EBI-301231	From a different organism.
TCEB2	Q15370	5	EBI-779991,EBI-301238	From a different organism.
UBL4A	P11441	2	EBI-779991,EBI-356983	From a different organism.
UBR2	Q8IWV8	3	EBI-779991,EBI-1237260	From a different organism.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 192

192

Virion infectivity factor

PRO_0000042762

Chain

1 – 150

150

Virion infectivity factor p17

PRO_0000042763

Chain

151 – 192

42

Virion infectivity factor p7

PRO_0000042764

Regions

Region

14 – 17

4

Interaction with host APOBEC3F; F1-box By similarity

Region

40 – 44

5

Interaction with host APOBEC3G; G-box By similarity

Region

54 – 72

19

Interaction with host APOBEC3F and APOBEC3G; FG-box By similarity

Region

74 – 79

6

Interaction with host APOBEC3F; F2-box By similarity

Region

75 – 114

40

RNA-binding Potential

Region

151 – 164

14

Multimerization

Region

171 – 172

2

Membrane association

Motif

108 – 139

32

HCCH motif

Motif

144 – 153

10

BC-box-like motif

Sites

Site

150 – 151

2

Cleavage in virion (by viral protease)

Amino acid modifications

Modified residue

96

1

Phosphothreonine; by host MAP4K1 By similarity

Modified residue

144

1

Phosphoserine; by host By similarity

Modified residue

165

1

Phosphoserine; by host MAP4K1 By similarity

Modified residue

188

1

Phosphothreonine; by host By similarity

Natural variations

Natural variant

90 – 93

4

RKKR → KKRK in strain: Clinical isolate; from an asymptomatic patient; Vif is mislocalized to the nucleus and non functional.

Experimental info

Mutagenesis

5 – 6

2

WQ → AA: 44% loss of viral infectivity.

Mutagenesis

12 – 13

2

QV → AA: No effect on viral infectivity.

Mutagenesis

16 – 18

3

MRI → AAA: 29% loss of viral infectivity. Ref.5

Mutagenesis

23 – 24

2

RL → AA: 14% loss of viral infectivity.

Mutagenesis

29 – 31

3

MYI → AAV: 59% loss of viral infectivity. Ref.5

Mutagenesis

33 – 34

2

RK → AA: 35% loss of viral infectivity.

Mutagenesis

38 – 40

3

WFY → AAA: 94% loss of viral infectivity. Ref.5

Mutagenesis

43 – 44

2

HY → AA: 95% loss of viral infectivity.

Mutagenesis

53 – 54

2

SE → AA: 39% loss of viral infectivity.

Mutagenesis

58 – 59

2

PL → AA: 45% loss of viral infectivity.

Mutagenesis

69 – 70

2

YW → AA: 97% loss of viral infectivity.

Mutagenesis

73 – 74

2

HT → AA: No effect onviral infectivity.

Mutagenesis

80 – 81

2

HL → AA: 19% loss of viral infectivity.

Mutagenesis

86 – 87

2

SI → AA: 42% loss of viral infectivity.

Mutagenesis

90 – 92

3

RKK → AAA: No effect on viral infectivity. Ref.5

Mutagenesis

97 – 98

2

QV → AA: 27% loss of viral infectivity.

Mutagenesis

105 – 107

3

QLI → AAV: 98% loss of viral infectivity. Ref.5

Mutagenesis

108

1

H → L: Complete loss of interaction with CUL5. Ref.16

Mutagenesis

111 – 112

2

YF → AA: 93% loss of viral infectivity.

Mutagenesis

114

1

C → S: 98% loss of viral infectivity. Complete loss of interaction with CUL5. Ref.5 Ref.14 Ref.16

Mutagenesis

121 – 123

3

RNT → AAA: 35% increase of viral infectivity. Ref.5

Mutagenesis

127 – 128

2

RI → AA: 10% loss of viral infectivity.

Mutagenesis

133

1

C → S: 95% loss of viral infectivity. Complete loss of interaction with CUL5. Ref.5 Ref.14 Ref.16

Mutagenesis

135 – 136

2

YQ → AA: 73% loss of viral infectivity.

Mutagenesis

139

1

H → L: Complete loss of interaction with CUL5. Ref.16

Mutagenesis

140 – 141

2

NK → AA: 68% loss of viral infectivity.

Mutagenesis

144 – 146

3

SLQ → AAA: 93% loss of viral infectivity. Ref.5 Ref.13

Mutagenesis

144

1

S → A: 25% loss of interaction with CUL5y. Ref.13

Mutagenesis

145

1

L → A: Complete loss of interaction with CUL5. Ref.13

Mutagenesis

146

1

Q → A: 90% loss of interaction with CUL5. Ref.13

Mutagenesis

147 – 148

2

YL → AA: 40% loss of viral infectivity. Ref.13

Mutagenesis

147

1

Y → A: 40% loss of interaction with CUL5. Ref.13

Mutagenesis

148

1

L → A: 35% loss of interaction with CUL5. Ref.13

Mutagenesis

149 – 151

3

ALA → RKS: Complete loss of processing between p17 and p7. Complete loss of replication. Ref.9 Ref.13

Mutagenesis

149

1

A → G: 75% loss of CUL5 binding activity. Ref.13

Mutagenesis

150

1

L → A: 90% loss of CUL5 binding activity. Ref.13

Mutagenesis

151

1

A → E: No effect on processing between p17 and p7.

Mutagenesis

151

1

A → N: Slightly increased processing between p17 and p7.

Mutagenesis

151

1

A → P: Increased processing between p17 and p7.

Mutagenesis

151

1

A → Y: Partial loss of processing between p17 and p7.

Mutagenesis

156 – 158

3

PKQ → AAA: No effect on viral infectivity. Ref.5

Mutagenesis

157

1

K → A: No effect viral infectivity. Ref.5

Mutagenesis

158 – 160

3

QIK → AAA: 9% loss of viral infectivity. Ref.5

Mutagenesis

160

1

K → A: 33% loss of viral infectivity.

Mutagenesis

161 – 164

4

PPLP → APLA: 88% loss of viral infectivity. Ref.5

Mutagenesis

161 – 163

3

PPL → AAA: 97% loss of viral infectivity.

Mutagenesis

161

1

P → A: 27% loss of viral infectivity.

Mutagenesis

162

1

P → A: No effect viral infectivity.

Mutagenesis

163

1

L → A: 26% loss of viral infectivity.

Mutagenesis

164

1

P → A: 63% loss of viral infectivity.

Mutagenesis

165

1

S → A: 67% loss of viral infectivity. Ref.5

Mutagenesis

166

1

V → A: 20% loss of viral infectivity. Ref.5

Mutagenesis

169 – 170

2

LT → AA: 42% loss of viral infectivity.

Mutagenesis

180 – 181

2

TK → AA: 5% loss of viral infectivity.

Mutagenesis

189 – 190

2

MN → AA: 4% loss of viral infectivity.

Secondary structure

1

.

.

.

192

Helix Strand Turn

Details...

Helix

145 – 154

10

Sequences

	Sequence		Length	Mass (Da)
	P12504 [UniParc]. Last modified October 1, 1989. Version 1. Checksum: 2830B3233E8ECD16	FASTA	192	22,699
	10 20 30 40 50 60 MENRWQVMIV WQVDRMRINT WKRLVKHHMY ISRKAKDWFY RHHYESTNPK ISSEVHIPLG 70 80 90 100 110 120 DAKLVITTYW GLHTGERDWH LGQGVSIEWR KKRYSTQVDP DLADQLIHLH YFDCFSESAI 130 140 150 160 170 180 RNTILGRIVS PRCEYQAGHN KVGSLQYLAL AALIKPKQIK PPLPSVRKLT EDRWNKPQKT 190 KGHRGSHTMN GH

References

[1]	Buckler C.E., Buckler-White A.J., Willey R.L., McCoy J. Submitted (JUN-1988) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA]. Strain: Clone pNL4-3.
[2]	Theodore T., Buckler-White A.J. Submitted (OCT-1992) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[3]	"Expression of human immunodeficiency virus type 1 vif and vpr mRNAs is Rev-dependent and regulated by splicing." Schwartz S., Felber B.K., Pavlakis G.N. Virology 183:677-686(1991) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[4]	"Role of vif during packing of the core of HIV-1." Hoglund S., Ohagen A., Lawrence K., Gabuzda D. Virology 201:349-355(1994) [PubMed] [Europe PMC] [Abstract] Cited for: ROLE IN VIRION MORPHOLOGY.
[5]	"Mutational analysis of the human immunodeficiency virus type 1 Vif protein." Simon J.H., Sheehy A.M., Carpenter E.A., Fouchier R.A., Malim M.H. J. Virol. 73:2675-2681(1999) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF 5-TRP-GLN-6; 12-GLN-VAL-13; 16-MET--ILE-18; 23-ARG-LEU-24; 29-MET--ILE-31; 33-ARG-LYS-34; 38-TRP--TYR-40; 43-HIS-TYR-44; 53-SER-GLU-54; 58-PRO-LEU-59; 69-TYR-TRP-70; 73-HIS-THR-74; 80-HIS-LEU-81; 86-SER-ILE-87; 90-ARG--LYS-92; 97-GLN-VAL-98; 105-GLN--ILE-107; 111-TYR-PHE-112; CYS-114; 121-ARG--THR-123; 127-ARG-ILE-128; CYS-133; 135-TYR-GLN-136; 140-ASN-LYS-141; 144-SER--GLN-146; 147-TYR-LEU-148; 156-PRO--GLN-158; LYS-157; 158-GLN--LYS-160; 161-PRO--LEU-164; SER-165; VAL-166; 169-LEU-THR-170; 180-THR-LYS-181 AND 189-MET-ASN-190.
[6]	"The multimerization of human immunodeficiency virus type I Vif protein: a requirement for Vif function in the viral life cycle." Yang S., Sun Y., Zhang H. J. Biol. Chem. 276:4889-4893(2001) [PubMed] [Europe PMC] [Abstract] Cited for: MULTIMERIZATION.
[7]	"Human immunodeficiency virus type 1 Vif protein is packaged into the nucleoprotein complex through an interaction with viral genomic RNA." Khan M.A., Aberham C., Kao S., Akari H., Gorelick R., Bour S., Strebel K. J. Virol. 75:7252-7265(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NUCLEOPROTEIN.
[8]	"The tyrosine kinase Hck is an inhibitor of HIV-1 replication counteracted by the viral vif protein." Hassaine G., Courcoul M., Bessou G., Barthalay Y., Picard C., Olive D., Collette Y., Vigne R., Decroly E. J. Biol. Chem. 276:16885-16893(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN HCK.
[9]	"Intravirion processing of the human immunodeficiency virus type 1 Vif protein by the viral protease may be correlated with Vif function." Khan M.A., Akari H., Kao S., Aberham C., Davis D., Buckler-White A., Strebel K. J. Virol. 76:9112-9123(2002) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-9 AND 151-162, CLEAVAGE BY VIRAL PROTEASE, MUTAGENESIS OF 149-ALA--ALA-151.
[10]	"The human immunodeficiency virus type 1 Vif protein reduces intracellular expression and inhibits packaging of APOBEC3G (CEM15), a cellular inhibitor of virus infectivity." Kao S., Khan M.A., Miyagi E., Plishka R., Buckler-White A., Strebel K. J. Virol. 77:11398-11407(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[11]	"The role of Vif during HIV-1 infection: interaction with novel host cellular factors." Lake J.A., Carr J., Feng F., Mundy L., Burrell C., Li P. J. Clin. Virol. 26:143-152(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN SAT.
[12]	"HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation." Marin M., Rose K.M., Kozak S.L., Kabat D. Nat. Med. 9:1398-1403(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN APOBEC3G.
[13]	"Phosphorylation of a novel SOCS-box regulates assembly of the HIV-1 Vif-Cul5 complex that promotes APOBEC3G degradation." Mehle A., Goncalves J., Santa-Marta M., McPike M., Gabuzda D. Genes Dev. 18:2861-2866(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN CUL5 AND ELONGIN BC COMPLEX, MUTAGENESIS OF SER-144; LEU-145; GLN-146; TYR-147; LEU-148; ALA-149 AND LEU-150.
[14]	"Vif overcomes the innate antiviral activity of APOBEC3G by promoting its degradation in the ubiquitin-proteasome pathway." Mehle A., Strack B., Ancuta P., Zhang C., McPike M., Gabuzda D. J. Biol. Chem. 279:7792-7798(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN APOBEC3G, MUTAGENESIS OF CYS-114 AND CYS-133.
[15]	"Ring finger protein ZIN interacts with human immunodeficiency virus type 1 Vif." Feng F., Davis A., Lake J.A., Carr J., Xia W., Burrell C., Li P. J. Virol. 78:10574-10581(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN UBCE7IP1.
[16]	"Primate lentiviral virion infectivity factors are substrate receptors that assemble with cullin 5-E3 ligase through a HCCH motif to suppress APOBEC3G." Luo K., Xiao Z., Ehrlich E., Yu Y., Liu B., Zheng S., Yu X.-F. Proc. Natl. Acad. Sci. U.S.A. 102:11444-11449(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN CUL5, MUTAGENESIS OF HIS-108; CYS-114; CYS-133 AND HIS-139.
[17]	"Nuclear localization of HIV type 1 Vif isolated from a long-term asymptomatic individual and potential role in virus attenuation." Farrow M.A., Somasundaran M., Zhang C., Gabuzda D., Sullivan J.L., Greenough T.C. AIDS Res. Hum. Retroviruses 21:565-574(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT 90-LYS--LYS-93. Strain: Clinical Isolate.
[18]	"The viral infectivity factor (Vif) of HIV-1 unveiled." Rose K.M., Marin M., Kozak S.L., Kabat D. Trends Mol. Med. 10:291-297(2004) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M19921 Genomic RNA. Translation: AAA44989.1.
M38431 Genomic RNA. Translation: AAB04038.1.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3DCG	X-ray	2.40	E/F	139-176	[»]

ProteinModelPortal

P12504.

ModBase

Search...

Protein-protein interaction databases

IntAct

P12504. 29 interactions.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Enzyme and pathway databases

Reactome

REACT_116125. Disease.

Family and domain databases

InterPro

IPR000475. Viral_infect.
[Graphical view]

Pfam

PF00559. Vif. 1 hit.
[Graphical view]

PRINTS

PR00349. VIRIONINFFCT.

ProtoNet

Search...

Other

EvolutionaryTrace

P12504.

Entry information

Entry name

VIF_HV1N5

Accession

Primary (citable) accession number: P12504

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1989
Last sequence update:	October 1, 1989
Last modified:	May 1, 2013
This is version 86 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Viral Protein Annotation Program