View source for Viral infectivity factor

{{Short description|Protein found in lentiviruses}}
{{Infobox protein family
|image=Crystal Structure of the HIV Vif BC-box in Complex with Human ElonginB and ElonginC.png
|caption=HIV-1 Vif BC-box in Complex with Human ELOB and ELOC ({{PDB|3DCG}}).<ref name="pmid18562529"/>
|InterPro=IPR000475
|Pfam=PF00559
|Symbol=Vif
}}
'''Viral infectivity factor''', or Vif, is an [[accessory protein]] found in [[HIV]] and other [[lentivirus]]es. Its role is to disrupt the antiviral activity of the human [[enzyme]] [[APOBEC]] (specifically [[APOBEC3G]], "A3G" in short, and other A3 enzymes) by targeting it for [[ubiquitin]]ation and cellular degradation. APOBEC is a cytidine deaminase enzyme that mutates viral nucleic acids.

Despite the functional and (weak) structural similarities, Vif found in lentiviruses can function in quite different ways. For example, the [[HIV-1]] Vif ("Vif<sub>1</sub>" hereafter) and [[HIV-2]] Vif ("Vif<sub>2</sub>") attach to APOBEC from different ends of themselves and have a different spectrum of inhibition. As HIV-1 is older and more virulent, many more studies have been done on the Vif<sub>1</sub> than on the Vif<sub>2</sub>. Similarly, more studies have been done on the HIV/[[Simian immunodeficiency virus|SIV]] Vif than on any other lentiviral Vif.<ref name="pmid24942576">{{cite journal |last1=Smith |first1=JL |last2=Izumi |first2=T |last3=Borbet |first3=TC |last4=Hagedorn |first4=AN |last5=Pathak |first5=VK |title=HIV-1 and HIV-2 Vif interact with human APOBEC3 proteins using completely different determinants. |journal=Journal of Virology |date=1 September 2014 |volume=88 |issue=17 |pages=9893–908 |doi=10.1128/JVI.01318-14 |pmid=24942576 |pmc=4136346}}</ref>

== Mechanism ==
=== HIV-1===
Vif<sub>1</sub> is a 23-[[kilodalton]] protein that is essential for viral replication.  Vif<sub>1</sub> inhibits the cellular protein [[APOBEC3G]] from entering the virion during budding from a host cell by targeting it for proteasomal degradation. Vif<sub>1</sub> binds to A3G as well as the cellular Cullin5 [[E3 Ubiquitin Ligase]] ([[ELOB]]-[[ELOC]]-[[CUL5]]) and a [[CBFB]] cofactor so that the ligase can be hijacked to tag A3G for degradation.<ref name=penta>{{cite journal | vauthors = da Costa KS, Leal E, dos Santos AM, Lima e Lima AH, Alves CN, Lameira J | title = Structural analysis of viral infectivity factor of HIV type 1 and its interaction with A3G, EloC and EloB | journal = PLOS ONE | volume = 9 | issue = 2 | pages = e89116 | date = 2014-02-26 | pmid = 24586532 | pmc = 3935857 | doi = 10.1371/journal.pone.0089116 | editor-first = Lukasz | doi-access = free | editor-last = Kurgan | bibcode = 2014PLoSO...989116D }}</ref> The crystal Structure of the HIV-1 Vif BC-box in Complex with Human [[Elongin B]] and [[Elongin C]] was solved in 2008,<ref name="pmid18562529">{{cite journal | vauthors = Stanley BJ, Ehrlich ES, Short L, Yu Y, Xiao Z, Yu XF, Xiong Y | title = Structural insight into the human immunodeficiency virus Vif SOCS box and its role in human E3 ubiquitin ligase assembly | journal = Journal of Virology | volume = 82 | issue = 17 | pages = 8656–63 | date = September 2008 | pmid = 18562529 | pmc = 2519636 | doi = 10.1128/JVI.00767-08 }}</ref> and the structure of the full Vif<sub>1</sub>/E3 complex was solved in 2014.<ref>{{cite journal | vauthors = Guo Y, Dong L, Qiu X, Wang Y, Zhang B, Liu H, Yu Y, Zang Y, Yang M, Huang Z | title = Structural basis for hijacking CBF-β and CUL5 E3 ligase complex by HIV-1 Vif | journal = Nature | volume = 505 | issue = 7482 | pages = 229–33 | date = January 2014 | pmid = 24402281 | doi = 10.1038/nature12884 | bibcode = 2014Natur.505..229G | s2cid = 4446181 }}</ref>

In the absence of Vif, APOBEC3G causes hypermutation of the viral [[genome]], rendering it dead-on-arrival at the next host cell. APOBEC3G is thus a host defence to retroviral infection which HIV-1 has overcome by the acquisition of Vif.<ref name="pmid18036235">{{cite journal | vauthors = Miller JH, Presnyak V, Smith HC | title = The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G | journal = Retrovirology | volume = 4 | issue = 1 | pages = 81 | date = November 2007 | pmid = 18036235 | pmc = 2222665 | doi = 10.1186/1742-4690-4-81 | doi-access = free }}</ref>  Vif<sub>1</sub> is additionally able to inhibit human A3C, A3D, A3F, and A3H haplotype II,<ref name=pmid30558640>{{cite journal |last1=Anderson |first1=BD |last2=Ikeda |first2=T |last3=Moghadasi |first3=SA |last4=Martin |first4=AS |last5=Brown |first5=WL |last6=Harris |first6=RS |title=Natural APOBEC3C variants can elicit differential HIV-1 restriction activity. |journal=Retrovirology |date=17 December 2018 |volume=15 |issue=1 |pages=78 |doi=10.1186/s12977-018-0459-5 |pmid=30558640|pmc=6297987 |doi-access=free }}</ref> all of which can similarly be packaged and cause hypermutation in Vif-deficient HIV-1. Different surfaces on Vif<sub>1</sub> are used to bind A3C, A3F, and A3G.<ref name="pmid27581978">{{cite journal |last1=Zhang |first1=Z |last2=Gu |first2=Q |last3=Jaguva Vasudevan |first3=AA |last4=Jeyaraj |first4=M |last5=Schmidt |first5=S |last6=Zielonka |first6=J |last7=Perković |first7=M |last8=Heckel |first8=JO |last9=Cichutek |first9=K |last10=Häussinger |first10=D |last11=Smits |first11=SHJ |last12=Münk |first12=C |title=Vif Proteins from Diverse Human Immunodeficiency Virus/Simian Immunodeficiency Virus Lineages Have Distinct Binding Sites in A3C. |journal=Journal of Virology |date=15 November 2016 |volume=90 |issue=22 |pages=10193–10208 |doi=10.1128/JVI.01497-16 |pmid=27581978|pmc=5105656}}</ref>

Vif may still be able to inhibit A3 in ways independent of degradation. Vif<sub>1</sub> seems to reduce the amount of A3 proteins (including A3D/G/F) packaged in the virion, and to slow down the action of any A3G that does make it in.<ref name="pmid33916704">{{cite journal |last1=Stupfler |first1=B |last2=Verriez |first2=C |last3=Gallois-Montbrun |first3=S |last4=Marquet |first4=R |last5=Paillart |first5=JC |title=Degradation-Independent Inhibition of APOBEC3G by the HIV-1 Vif Protein. |journal=Viruses |date=3 April 2021 |volume=13 |issue=4 |page=617 |doi=10.3390/v13040617 |pmid=33916704 |pmc=8066197|doi-access=free }}</ref>

Vif<sub>1</sub> was considered as a [[phosphoprotein]] and [[phosphorylation]] seemed to be required for viral infectivity.<ref>{{cite journal | vauthors = Yang X, Gabuzda D | title = Mitogen-activated protein kinase phosphorylates and regulates the HIV-1 Vif protein | journal = The Journal of Biological Chemistry | volume = 273 | issue = 45 | pages = 29879–87 | date = November 1998 | pmid = 9792705 | doi = 10.1074/jbc.273.45.29879 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Yang X, Goncalves J, Gabuzda D | title = Phosphorylation of Vif and its role in HIV-1 replication | journal = The Journal of Biological Chemistry | volume = 271 | issue = 17 | pages = 10121–9 | date = April 1996 | pmid = 8626571 | doi = 10.1074/jbc.271.17.10121 | doi-access = free }}</ref><ref name="Raja 101805">{{Cite journal |last1=Raja |first1=Rameez |last2=Wang |first2=Chenyao |last3=Mishra |first3=Ritu |last4=Das |first4=Arundhoti |last5=Ali |first5=Amjad |last6=Banerjea |first6=Akhil C. |date=2022-03-05 |title=Host AKT-mediated phosphorylation of HIV-1 accessory protein Vif potentiates infectivity via enhanced degradation of the restriction factor APOBEC3G |journal=The Journal of Biological Chemistry |volume=298 |issue=4 |pages=101805 |doi=10.1016/j.jbc.2022.101805 |issn=1083-351X |pmid=35259395|pmc=8980627 |doi-access=free }}</ref> But recent studies with the use of metabolic labelling demonstrated that serine/threonine phosphorylation of Vif<sub>1</sub> and A3G is not required for the interaction of Vif<sub>1</sub> with A3G for Vif dependent degradation of A3G and the antiviral activity of A3G.<ref>{{cite journal | vauthors = Kopietz F, Jaguva Vasudevan AA, Krämer M, Muckenfuss H, Sanzenbacher R, Cichutek K, Flory E, Münk C | title = Interaction of human immunodeficiency virus type 1 Vif with APOBEC3G is not dependent on serine/threonine phosphorylation status | journal = The Journal of General Virology | volume = 93 | issue = Pt 11 | pages = 2425–30 | date = November 2012 | pmid = 22894923 | doi = 10.1099/vir.0.043273-0 | url = http://vir.sgmjournals.org/content/93/Pt_11/2425.long | doi-access = free }}</ref> However, a recent study by Raja et al has shown that Host AKT-Mediated phosphorylation of HIV-1 Vif at Thr20 stabilizes it to enhance APOBEC3G degradation and potentiate HIV-1 infectivity.<ref name="Raja 101805"/>

===HIV-2===
Vif<sub>2</sub> is only about ~30% identical at the amino acid level to Vif<sub>1</sub>, a result of the evolutionary separation in different source species of the two viruses (see [[Subtypes of HIV]]). In 2014, it was discovered that Vif<sub>2</sub> attaches to A3G and A3F using very different residues compared to Vif<sub>1</sub>, and that it, unlike Vif<sub>1</sub>, cannot inhibit A3D at all.<ref name="pmid24942576"/> In 2016, it was found that Vif<sub>2</sub> also attaches to A3C differently.<ref name="pmid27581978"/> In 2021, it was found that Vif<sub>2</sub> inhibits A3B (which HIV-1 does not) and that A3B is able to inhibit a Vif-less HIV-2 (but not a Vif-less HIV-1). As A3B is also implicated in hypermutation in cancer, this discovery could lead to a way to slow down cancer cells.<ref>{{cite journal |last1=Bandarra |first1=S |last2=Miyagi |first2=E |last3=Ribeiro |first3=AC |last4=Gonçalves |first4=J |last5=Strebel |first5=K |last6=Barahona |first6=I |title=APOBEC3B Potently Restricts HIV-2 but Not HIV-1 in a Vif-Dependent Manner. |journal=Journal of Virology |date=9 November 2021 |volume=95 |issue=23 |pages=e0117021 |doi=10.1128/JVI.01170-21 |pmid=34523960|pmc=8577350 }}</ref>

No structure of Vif<sub>2</sub> can be found in the [[Protein Data Bank]]. However, it is known from the related Vif<sub>mac</sub> (SIV<sub>mac</sub> Vif) that it probably binds A3B in the same orientation as Vif<sub>1</sub> does for A3G.<ref>{{cite journal |last1=Wang |first1=J |last2=Shaban |first2=NM |last3=Land |first3=AM |last4=Brown |first4=WL |last5=Harris |first5=RS |title=Simian Immunodeficiency Virus Vif and Human APOBEC3B Interactions Resemble Those between HIV-1 Vif and Human APOBEC3G. |journal=Journal of Virology |date=15 June 2018 |volume=92 |issue=12 |doi=10.1128/JVI.00447-18 |pmid=29618650 |pmc=5974497}}</ref>

== Drug target ==
Ever since the 2000s, there has been interest in developing drugs that disarm the virus by inhibiting Vif.<ref name="pmid18036235"/> A 2018 review lists 17 small molecules capable of stopping viral replication by Vif inhibition, and categorized them into the functional categories of Vif multimerization targeting, A3G-Vif-targeting (two subcategories by the binding interface disrupted), Vif-EloC targeting, and A3G-upregulating. Two of the drugs were further checked for resistance potential. It turns out that the virus can become resistant in laboratory conditions after exposure to increasing amounts of either drug.<ref>{{cite journal |last1=Bennett |first1=RP |last2=Salter |first2=JD |last3=Smith |first3=HC |title=A New Class of Antiretroviral Enabling Innate Immunity by Protecting APOBEC3 from HIV Vif-Dependent Degradation. |journal=Trends in Molecular Medicine |date=May 2018 |volume=24 |issue=5 |pages=507–520 |doi=10.1016/j.molmed.2018.03.004 |pmid=29609878|pmc=7362305 }}</ref>

In July 2021, the Chinese [[National Medical Products Administration]] granted conditional approval to [[azvudine]], which claims to be a dual [[nucleoside reverse transcriptase inhibitor]] and HIV-1 Vif inhibitor.<ref name="Li2022">{{cite journal |last1=Li |first1=Guangdi |last2=Wang |first2=Yali |last3=De Clercq |first3=Erik |title=Approved HIV reverse transcriptase inhibitors in the past decade |journal=Acta Pharmaceutica Sinica B |date=April 2022 |volume=12 |issue=4 |pages=1567–1590 |doi=10.1016/j.apsb.2021.11.009|pmid=35847492 |pmc=9279714 }}</ref>

== In other species ==
Vif has been found in other Lentiviruses, including the [[Simian immunodeficiency virus]] (SIV), [[Feline immunodeficiency virus]] (FIV; {{Pfam|PF05851}}), [[Visna virus]] (MVV) and [[Caprine arthritis encephalitis virus]] ({{Pfam|PF07401}}).<ref>{{cite journal | vauthors = Zhao Z, Li Z, Huan C, Wang H, Su X, Zhang W | title = CAEV Vif Hijacks ElonginB/C, CYPA and Cullin5 to Assemble the E3 Ubiquitin Ligase Complex Stepwise to Degrade oaA3Z2-Z3 | journal = Frontiers in Microbiology | volume = 10 | pages = 565 | date = 2019 | pmid = 30941116 | pmc = 6434172 | doi = 10.3389/fmicb.2019.00565 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Gabuzda DH, Lawrence K, Langhoff E, Terwilliger E, Dorfman T, Haseltine WA, Sodroski J | title = Role of vif in replication of human immunodeficiency virus type 1 in CD4+ T lymphocytes | journal = Journal of Virology | volume = 66 | issue = 11 | pages = 6489–95 | date = November 1992 | doi = 10.1128/JVI.66.11.6489-6495.1992 | pmid = 1357189 | pmc = 240141 }}</ref> The mamallian APOBEC3 enzymes are in an arms race with Vifs found in those viruses, actively evolving and diversifying to escape inactivation. Most Vifs use CBFB with CRL complex (CUL2/5-RBX2-ELOB/C) as the cofactor/adapter, but [[Visna-maedi virus]] (MVV) uses [[Peptidylprolyl isomerase A|CYPA]] instead of CBFB. [[Bovine immunodeficiency virus]] Vif unusually requires none of such adapters.<ref>{{cite journal | vauthors = Nakano Y, Aso H, Soper A, Yamada E, Moriwaki M, Juarez-Fernandez G, Koyanagi Y, Sato K | title = A conflict of interest: the evolutionary arms race between mammalian APOBEC3 and lentiviral Vif | journal = Retrovirology | volume = 14 | issue = 1 | pages = 31 | date = May 2017 | pmid = 28482907 | pmc = 5422959 | doi = 10.1186/s12977-017-0355-4 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Konno Y, Nagaoka S, Kimura I, Yamamoto K, Kagawa Y, Kumata R, Aso H, Ueda MT, Nakagawa S, Kobayashi T, Koyanagi Y, Sato K | display-authors = 6 | title = New World feline APOBEC3 potently controls inter-genus lentiviral transmission | journal = Retrovirology | volume = 15 | issue = 1 | pages = 31 | date = April 2018 | pmid = 29636069 | doi = 10.1186/s12977-018-0414-5 | pmc = 5894237 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Yoshikawa R, Izumi T, Yamada E, Nakano Y, Misawa N, Ren F, Carpenter MA, Ikeda T, Münk C, Harris RS, Miyazawa T, Koyanagi Y, Sato K | display-authors = 6 | title = A Naturally Occurring Domestic Cat APOBEC3 Variant Confers Resistance to Feline Immunodeficiency Virus Infection | journal = Journal of Virology | volume = 90 | issue = 1 | pages = 474–85 | date = January 2016 | pmid = 26491161 | doi = 10.1128/JVI.02612-15 | pmc = 4702554 | doi-access = free }}</ref>

== References ==
{{Reflist|32em}}

== External links ==
* {{MeSH name|vif+Protein}}

{{Viral proteins}}

{{DEFAULTSORT:Viral Infectivity Factor}}
[[Category:Viral regulatory and accessory proteins]]