Viral infectivity factor explained

Viral infectivity factor, or Vif, is an accessory protein found in HIV and other lentiviruses. 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 ubiquitination 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 ("Vif1" hereafter) and HIV-2 Vif ("Vif2") 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 Vif1 than on the Vif2. Similarly, more studies have been done on the HIV/SIV Vif than on any other lentiviral Vif.[1]

Mechanism

HIV-1

Vif1 is a 23-kilodalton protein that is essential for viral replication. Vif1 inhibits the cellular protein APOBEC3G from entering the virion during budding from a host cell by targeting it for proteasomal degradation. Vif1 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.[2] The crystal Structure of the HIV-1 Vif BC-box in Complex with Human Elongin B and Elongin C was solved in 2008,[3] and the structure of the full Vif1/E3 complex was solved in 2014.[4]

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.[5] Vif1 is additionally able to inhibit human A3C, A3D, A3F, and A3H haplotype II,[6] all of which can similarly be packaged and cause hypermutation in Vif-deficient HIV-1. Different surfaces on Vif1 are used to bind A3C, A3F, and A3G.[7]

Vif may still be able to inhibit A3 in ways independent of degradation. Vif1 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.[8]

Vif1 was considered as a phosphoprotein and phosphorylation seemed to be required for viral infectivity.[9] [10] [11] But recent studies with the use of metabolic labelling demonstrated that serine/threonine phosphorylation of Vif1 and A3G is not required for the interaction of Vif1 with A3G for Vif dependent degradation of A3G and the antiviral activity of A3G.[12] 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.[11]

HIV-2

Vif2 is only about ~30% identical at the amino acid level to Vif1, a result of the evolutionary separation in different source species of the two viruses (see Subtypes of HIV). In 2014, it was discovered that Vif2 attaches to A3G and A3F using very different residues compared to Vif1, and that it, unlike Vif1, cannot inhibit A3D at all.[1] In 2016, it was found that Vif2 also attaches to A3C differently.[7] In 2021, it was found that Vif2 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.[13]

, no structure of Vif2 can be found in the Protein Data Bank. However, it is known from the related Vifmac (SIVmac Vif) that it probably binds A3B in the same orientation as Vif1 does for A3G.[14]

Drug target

Ever since the 2000s, there has been interest in developing drugs that disarm the virus by inhibiting Vif.[5] An 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.[15]

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.[16]

In other species

Vif has been found in other Lentiviruses, including the Simian immunodeficiency virus (SIV), Feline immunodeficiency virus (FIV;), Visna virus (MVV) and Caprine arthritis encephalitis virus .[17] [18] 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 CYPA instead of CBFB. Bovine immunodeficiency virus Vif unusually requires none of such adapters.[19] [20] [21]

Notes and References

  1. Smith . JL . Izumi . T . Borbet . TC . Hagedorn . AN . Pathak . VK . HIV-1 and HIV-2 Vif interact with human APOBEC3 proteins using completely different determinants. . Journal of Virology . 1 September 2014 . 88 . 17 . 9893–908 . 10.1128/JVI.01318-14 . 24942576 . 4136346.
  2. da Costa KS, Leal E, dos Santos AM, Lima e Lima AH, Alves CN, Lameira J . Structural analysis of viral infectivity factor of HIV type 1 and its interaction with A3G, EloC and EloB . PLOS ONE . 9 . 2 . e89116 . 2014-02-26 . 24586532 . 3935857 . 10.1371/journal.pone.0089116 . Lukasz . free . Kurgan . 2014PLoSO...989116D .
  3. Stanley BJ, Ehrlich ES, Short L, Yu Y, Xiao Z, Yu XF, Xiong Y . Structural insight into the human immunodeficiency virus Vif SOCS box and its role in human E3 ubiquitin ligase assembly . Journal of Virology . 82 . 17 . 8656–63 . September 2008 . 18562529 . 2519636 . 10.1128/JVI.00767-08 .
  4. Guo Y, Dong L, Qiu X, Wang Y, Zhang B, Liu H, Yu Y, Zang Y, Yang M, Huang Z . Structural basis for hijacking CBF-β and CUL5 E3 ligase complex by HIV-1 Vif . Nature . 505 . 7482 . 229–33 . January 2014 . 24402281 . 10.1038/nature12884 . 2014Natur.505..229G . 4446181 .
  5. Miller JH, Presnyak V, Smith HC . The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G . Retrovirology . 4 . 1 . 81 . November 2007 . 18036235 . 2222665 . 10.1186/1742-4690-4-81 . free .
  6. Anderson . BD . Ikeda . T . Moghadasi . SA . Martin . AS . Brown . WL . Harris . RS . Natural APOBEC3C variants can elicit differential HIV-1 restriction activity. . Retrovirology . 17 December 2018 . 15 . 1 . 78 . 10.1186/s12977-018-0459-5 . 30558640. 6297987 . free .
  7. Zhang . Z . Gu . Q . Jaguva Vasudevan . AA . Jeyaraj . M . Schmidt . S . Zielonka . J . Perković . M . Heckel . JO . Cichutek . K . Häussinger . D . Smits . SHJ . Münk . C . Vif Proteins from Diverse Human Immunodeficiency Virus/Simian Immunodeficiency Virus Lineages Have Distinct Binding Sites in A3C. . Journal of Virology . 15 November 2016 . 90 . 22 . 10193–10208 . 10.1128/JVI.01497-16 . 27581978. 5105656.
  8. Stupfler . B . Verriez . C . Gallois-Montbrun . S . Marquet . R . Paillart . JC . Degradation-Independent Inhibition of APOBEC3G by the HIV-1 Vif Protein. . Viruses . 3 April 2021 . 13 . 4 . 617 . 10.3390/v13040617 . 33916704 . 8066197. free .
  9. Yang X, Gabuzda D . Mitogen-activated protein kinase phosphorylates and regulates the HIV-1 Vif protein . The Journal of Biological Chemistry . 273 . 45 . 29879–87 . November 1998 . 9792705 . 10.1074/jbc.273.45.29879 . free .
  10. Yang X, Goncalves J, Gabuzda D . Phosphorylation of Vif and its role in HIV-1 replication . The Journal of Biological Chemistry . 271 . 17 . 10121–9 . April 1996 . 8626571 . 10.1074/jbc.271.17.10121 . free .
  11. Raja . Rameez . Wang . Chenyao . Mishra . Ritu . Das . Arundhoti . Ali . Amjad . Banerjea . Akhil C. . 2022-03-05 . Host AKT-mediated phosphorylation of HIV-1 accessory protein Vif potentiates infectivity via enhanced degradation of the restriction factor APOBEC3G . The Journal of Biological Chemistry . 298 . 4 . 101805 . 10.1016/j.jbc.2022.101805 . 1083-351X . 35259395. 8980627 . free .
  12. Kopietz F, Jaguva Vasudevan AA, Krämer M, Muckenfuss H, Sanzenbacher R, Cichutek K, Flory E, Münk C . Interaction of human immunodeficiency virus type 1 Vif with APOBEC3G is not dependent on serine/threonine phosphorylation status . The Journal of General Virology . 93 . Pt 11 . 2425–30 . November 2012 . 22894923 . 10.1099/vir.0.043273-0 . free .
  13. Bandarra . S . Miyagi . E . Ribeiro . AC . Gonçalves . J . Strebel . K . Barahona . I . APOBEC3B Potently Restricts HIV-2 but Not HIV-1 in a Vif-Dependent Manner. . Journal of Virology . 9 November 2021 . 95 . 23 . e0117021 . 10.1128/JVI.01170-21 . 34523960. 8577350 .
  14. Wang . J . Shaban . NM . Land . AM . Brown . WL . Harris . RS . Simian Immunodeficiency Virus Vif and Human APOBEC3B Interactions Resemble Those between HIV-1 Vif and Human APOBEC3G. . Journal of Virology . 15 June 2018 . 92 . 12 . 10.1128/JVI.00447-18 . 29618650 . 5974497.
  15. Bennett . RP . Salter . JD . Smith . HC . A New Class of Antiretroviral Enabling Innate Immunity by Protecting APOBEC3 from HIV Vif-Dependent Degradation. . Trends in Molecular Medicine . May 2018 . 24 . 5 . 507–520 . 10.1016/j.molmed.2018.03.004 . 29609878. 7362305 .
  16. Li . Guangdi . Wang . Yali . De Clercq . Erik . Approved HIV reverse transcriptase inhibitors in the past decade . Acta Pharmaceutica Sinica B . April 2022 . 12 . 4 . 1567–1590 . 10.1016/j.apsb.2021.11.009. 35847492 . 9279714 .
  17. Zhao Z, Li Z, Huan C, Wang H, Su X, Zhang W . CAEV Vif Hijacks ElonginB/C, CYPA and Cullin5 to Assemble the E3 Ubiquitin Ligase Complex Stepwise to Degrade oaA3Z2-Z3 . Frontiers in Microbiology . 10 . 565 . 2019 . 30941116 . 6434172 . 10.3389/fmicb.2019.00565 . free .
  18. Gabuzda DH, Lawrence K, Langhoff E, Terwilliger E, Dorfman T, Haseltine WA, Sodroski J . Role of vif in replication of human immunodeficiency virus type 1 in CD4+ T lymphocytes . Journal of Virology . 66 . 11 . 6489–95 . November 1992 . 10.1128/JVI.66.11.6489-6495.1992 . 1357189 . 240141 .
  19. Nakano Y, Aso H, Soper A, Yamada E, Moriwaki M, Juarez-Fernandez G, Koyanagi Y, Sato K . A conflict of interest: the evolutionary arms race between mammalian APOBEC3 and lentiviral Vif . Retrovirology . 14 . 1 . 31 . May 2017 . 28482907 . 5422959 . 10.1186/s12977-017-0355-4 . free .
  20. Konno Y, Nagaoka S, Kimura I, Yamamoto K, Kagawa Y, Kumata R, Aso H, Ueda MT, Nakagawa S, Kobayashi T, Koyanagi Y, Sato K . 6 . New World feline APOBEC3 potently controls inter-genus lentiviral transmission . Retrovirology . 15 . 1 . 31 . April 2018 . 29636069 . 10.1186/s12977-018-0414-5 . 5894237 . free .
  21. 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 . 6 . A Naturally Occurring Domestic Cat APOBEC3 Variant Confers Resistance to Feline Immunodeficiency Virus Infection . Journal of Virology . 90 . 1 . 474–85 . January 2016 . 26491161 . 10.1128/JVI.02612-15 . 4702554 . free .

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