Reviewed, UniProtKB/Swiss-Prot P12504 (VIF_HV1N5)

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- Recommended name:
            Virion infectivity factor p17
    2- Recommended name:
            Virion infectivity factor p7

Gene names

Name:

vif

Organism

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

Taxonomic identifier

11698 [NCBI]

Taxonomic lineage

Viruses › Retro-transcribing viruses › Retroviridae › Orthoretrovirinae › Lentivirus › Primate lentivirus group

Virus host

Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	192 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Counteracts the innate antiviral activity of APOBEC3G. Forms a complex with host APOBEC3G thus preventing the entry of this lethally hypermutating enzyme into progeny virions. Functions as an adapter molecule, recruiting APOBEC3G to the ubiquitin-proteasome machinery. Targets APOBEC3G for degradation through the assembly with elongin BC complex, CUL5 and RBX1. Binds viral RNA and affects the stability of viral nucleoprotein core. May play a role in viral morphology. Interacts with host ABCE1, which seems to be involved in lentiviruses capsid formation and displays RNase L inhibitor activity. This interaction may play a role in protecting viral RNA from damage during viral assembly. May interact with host SAT, which is a regulator of polyamine cell level. This interaction may be relevant since polyamines affect viral RNA properties.
Subunit structure	Homomultimer; in vitro and presumably in vivo. Interacts with viral Pr55Gag precursor, human APOBEC3G, UBCE7IP1 isoform 3/ZIN, ABCE1 and possibly with SAT. Binds human HCK in vitro, but since this protein does not seem to be expressed in CD4+ cells, the significance of this interaction remains unclear. The interaction between Vif and APOBEC3G is species-specific, which may play a role in restricting the replication of HIV to humans. Forms an E3 ligase complex by interacting with human CUL5 and elongin BC complex (TCEB1 and TCEB2).
Subcellular location	Cytoplasm. 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.
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	Cell membrane Cytoplasm Membrane Virion
Disease	AIDS
Ligand	RNA-binding
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	initiation of viral infection Inferred from Experiment. Source: Reactome interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW provirus integration Inferred from Experiment. Source: Reactome ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytosol Ref.12 Inferred from Experiment. Source: Reactome plasma membrane Inferred from electronic annotation. Source: UniProtKB-KW virion Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	RNA binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Ref.8 Ref.15 Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
APOBEC3G	Q9HC16	1	EBI-779991,EBI-717839	From a different organism.
HCK	P08631	3	EBI-779991,EBI-346340	From a different organism.
RNF216	Q9NWF9-3	2	EBI-779991,EBI-723337	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	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 MAP4K1 By similarity
	Modified residue	144	1	Phosphoserine By similarity
	Modified residue	165	1	Phosphoserine; by MAP4K1 By similarity
	Modified residue	188	1	Phosphothreonine 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
	Mutagenesis	23 – 24	2	RL → AA: 14% loss of viral infectivity
	Mutagenesis	29 – 31	3	MYI → AAV: 59% loss of viral infectivity
	Mutagenesis	33 – 34	2	RK → AA: 35% loss of viral infectivity
	Mutagenesis	38 – 40	3	WFY → AAA: 94% loss of viral infectivity
	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
	Mutagenesis	97 – 98	2	QV → AA: 27% loss of viral infectivity
	Mutagenesis	105 – 107	3	QLI → AAV: 98% loss of viral infectivity
	Mutagenesis	108	1	H → L: Complete loss of interaction with CUL5
	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
	Mutagenesis	121 – 123	3	RNT → AAA: 35% increase of viral infectivity
	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
	Mutagenesis	135 – 136	2	YQ → AA: 73% loss of viral infectivity
	Mutagenesis	139	1	H → L: Complete loss of interaction with CUL5
	Mutagenesis	140 – 141	2	NK → AA: 68% loss of viral infectivity
	Mutagenesis	144 – 146	3	SLQ → AAA: 93% loss of viral infectivity
	Mutagenesis	144	1	S → A: 25% loss of interaction with CUL5y
	Mutagenesis	145	1	L → A: Complete loss of interaction with CUL5
	Mutagenesis	146	1	Q → A: 90% loss of interaction with CUL5
	Mutagenesis	147 – 148	2	YL → AA: 40% loss of viral infectivity
	Mutagenesis	147	1	Y → A: 40% loss of interaction with CUL5
	Mutagenesis	148	1	L → A: 35% loss of interaction with CUL5
	Mutagenesis	149 – 151	3	ALA → RKS: Complete loss of processing between p17 and p7. Complete loss of replication
	Mutagenesis	149	1	A → G: 75% loss of CUL5 binding activity
	Mutagenesis	150	1	L → A: 90% loss of CUL5 binding activity
	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
	Mutagenesis	157	1	K → A: No effect viral infectivity
	Mutagenesis	158 – 160	3	QIK → AAA: 9% loss of viral infectivity
	Mutagenesis	160	1	K → A: 33% loss of viral infectivity
	Mutagenesis	161 – 164	4	PPLP → APLA: 88% loss of viral infectivity
	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
	Mutagenesis	166	1	V → A: 20% loss of viral infectivity
	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

Sequences

	Sequence		Length	Mass (Da)
	P12504-1 [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: 1830183] [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: 8184544] [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: 10074113] [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: 11071884] [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: 11461998] [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: 11278465] [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: 12186895] [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: 14557625] [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: 12600646] [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: 14528301] [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: 15574592] [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: 14672928] [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: 15367624] [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: 16076960] [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: 15989462] [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: 15177194] [Abstract] Cited for: REVIEW.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	M19921 Genomic RNA. Translation: AAA44989.1. M38431 Genomic RNA. Translation: AAB04038.1.
3D structure databases