Problems of VirologyProblems of VirologyВопросы вирусологии0507-40882411-2097Central Research Institute for Epidemiology1659710.36233/0507-4088-207klgwakREVIEWSОБЗОРЫReview ArticleCellular proteins as potential targets for antiretroviral therapyКлеточные белки – потенциальные мишени антиретровирусной терапииhttps://orcid.org/0000-0001-5481-8957BobkovaMarina R.БобковаМарина Ридовна
Russian Federation

Dr. Sci. (Biol.), Chief Researcher of the laboratory of biology of lentiviruses I. Mechnikov Research Institute for Vaccines and Sera, Moscow, Russia

д-р биол. наук, главный специалист лаборатории биологии лентивирусов ФГБНУ «НИИ вакцин и сывороток им. И.И. Мечникова», Москва, Россия

mrbobkova@mail.ruI. Mechnikov Research Institute for Vaccines and SeraФГБНУ «Научно-исследовательский институт вакцин и сывороток им. И.И. Мечникова»2612202368648850405122023Copyright ©; 2023, Bobkova M.R.Copyright ©; 2023, Бобкова М.Р.2023Bobkova M.R.Бобкова М.Р.https://creativecommons.org/licenses/by/4.0https://virusjour.crie.ru/jour/article/view/16597

The review article conducts an in-depth analysis of information gleaned from a comprehensive literature search across Scopus, Web of Science, and MedLine databases. The focal point of this search revolves around the identification and exploration of the mechanisms orchestrated by host cell factors in the replication cycle of the human immunodeficiency virus (HIV-1, Retroviridae: Orthoretrovirinae: Lentivirus: Human immunodeficiency virus-1). The article delves into two primary categories of proteins, namely HIV dependence factors (such as CypA, LEDGF, TSG101) and restriction factors (including SERINС5, TRIM5α, APOBEC3G), providing illustrative examples. The current understanding of the functioning mechanisms of these proteins is elucidated, and an evaluation is presented on the potential development of drugs for treating HIV infection. These drugs aim to either inhibit or stimulate the activity of host factors, offering insights into promising avenues for future research and therapeutic advancements.

Обзорная статья содержит анализ информации, полученной в результате поиска литературы по базам данных Scopus, Web of Science, MedLine. Тема поиска – идентификация и изучение механизмов действия факторов хозяйской клетки, участвующих в цикле репликации вируса иммунодефицита человека (ВИЧ, Retroviridae: Orthoretrovirinae: Lentivirus: Human immunodeficiency virus-1). Приведены примеры двух основных групп белков – факторов зависимости ВИЧ (CypA, LEDGF, TSG101 и др.) и факторов рестрикции (SERINС5, TRIM5α, APOBEC3G и др.); описано современное состояние представлений о механизмах их функционирования. Дана оценка перспектив разработки лекарственных средств для лечения ВИЧ-инфекции, направленных на ингибирование либо стимуляцию активности хозяйских факторов.

HIVhost proteinsdependence factorsrestriction factorsreviewВИЧхозяйские белкифакторы зависимостифакторы рестрикцииобзорРоссийский научный фондThe Russian Science FoundationNo. 22-15-00117Roa-Linares V.C., Escudero-Florez M., Vicente-Manzanares M., Gallego-Gomez J.C. Host cell targets for unconventional antivirals against RNA viruses. Viruses. 2023; 15(3): 776. https://doi.org/10.3390/v15030776Bolinger C., Boris-Lawrie K. Mechanisms employed by retroviruses to exploit host factors for translational control of a complicated proteome. Retrovirology. 2009; 6: 8. https://doi.org/10.1186/1742-4690-6-8Colomer-Lluch M., Ruiz A., Moris A., Prado J.G. Restriction factors: from intrinsic viral restriction to shaping cellular immunity against HIV-1. Front. Immunol. 2018; 9: 2876. https://doi.org/10.3389/fimmu.2018.02876Ghimire D., Rai M., Gaur R. Novel host restriction factors implicated in HIV-1 replication. J. Gen. Virol. 2018; 99(4): 435–46. https://doi.org/10.1099/jgv.0.001026Puhl A.C., Garzino Demo A., Makarov V.A., Ekins S. New targets for HIV drug discovery. Drug Discov. Today. 2019; 24(5): 1139–47. https://doi.org/10.1016/j.drudis.2019.03.013Schaller T., Herold N. The early bird catches the worm – can evolution teach us lessons in fighting HIV? Curr. HIV Res. 2016; 14(3): 183–210. https://doi.org/10.2174/1570162x14999160224094914Shukla E., Chauhan R. Host-HIV-1 interactome: a quest for novel therapeutic intervention. Cells. 2019; 8(10): 1155. https://doi.org/10.3390/cells8101155Brass A.L., Dykxhoorn D.M., Benita Y., Yan N., Engelman A., Xavier R.J., et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science. 2008; 319(5865): 921–6. https://doi.org/10.1126/science.1152725Goffinet C. Cellular antiviral factors that target particle infectivity of HIV-1. Curr. HIV Res. 2016; 14(3): 211–6. https://doi.org/10.2174/1570162x14666151216145521Alvarez V., Lopez-Larrea C., Coto E. Mutational analysis of the CCR5 and CXCR4 genes (HIV-1 co-receptors) in resistance to HIV-1 infection and AIDS development among intravenous drug users. Hum. Genet. 1998; 102(4): 483–6. https://doi.org/10.1007/s004390050726Cohn S.K. Jr., Weaver L.T. The black death and AIDS: CCR5-Delta32 in genetics and history. QJM. 2006; 99(8): 497–503. https://doi.org/10.1093/qjmed/hcl076Dean M., Carrington M., Winkler C., Huttley G.A., Smith M.W., Allikmets R., et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science. 1996; 273(5283): 1856–62. https://doi.org/10.1126/science.273.5283.1856Tsui C.K., Gupta A., Bassik M.C. Finding host targets for HIV therapy. Nat. Genet. 2017; 49(2): 175–6. https://doi.org/10.1038/ng.3777Park R.J., Wang T., Koundakjian D., Hultquist J.F., Lamothe-Molina P., Monel B., et al. A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors. Nat. Gen. 2017; 49(2): 193–203. https://doi.org/10.1038/ng.3741Blumenthal R., Durell S., Viard M. HIV entry and envelope glycoprotein-mediated fusion. J. Biol. Chem. 2012; 287(49): 40841–9. https://doi.org/10.1074/jbc.r112.406272Hadpech S., Moonmuang S., Chupradit K., Yasamut U., Tayapiwatana C. Updating on roles of HIV intrinsic factors: A review of their antiviral mechanisms and emerging functions. Intervirology. 2022; 65(2): 67–79. https://doi.org/10.1159/000519241Gonzalez-Enriquez G.V., Escoto-Delgadillo M., Vazquez-Valls E., Torres-Mendoza B.M. SERINC as a Restriction Factor to Inhibit Viral Infectivity and the Interaction with HIV. J. Immunol. Res. 2017; 2017: 1548905. https://doi.org/10.1155/2017/1548905Tedbury P.R., Sarafianos S.G. Exposing HIV’s weaknesses. J. Biol. Chem. 2017; 292(14): 6027–8. https://doi.org/10.1074/jbc.h117.777714Lopez Hernandez M., Lopez De Lucio S. Accessory regulatory proteins of HIV-1 and host restriction factors interactions. Biomed. J. Sci. Tech. Res. 2020; 31(4): 24308–12. https://doi.org/10.26717/BJSTR.2020.31.005120Huérfano S., Šroller V., Bruštíková K., Horníková L., Forstová J. The interplay between viruses and host DNA sensors. Viruses. 2022; 14(4): 666. https://doi.org/10.3390/v14040666Yin X., Langer S., Zhang Z., Herbert K.M., Yoh S., König R., et al. Sensor sensibility-HIV-1 and the innate immune response. Cells. 2020; 9(1): 254. https://doi.org/10.3390/cells9010254Yamashita M., Engelman A.N. Capsid-dependent host factors in HIV-1 infection. Trends Microbiol. 2017; 25(9): 741–55. https://doi.org/10.1016/j.tim.2017.04.004Ramdas P., Sahu A.K., Mishra T., Bhardwaj V., Chande A. From entry to egress: strategic exploitation of the cellular processes by HIV-1. Front. Microbiol. 2020; 11: 559792. https://doi.org/10.3389/fmicb.2020.559792Malim M.H., Bieniasz P.D. HIV restriction factors and mechanisms of evasion. Cold Spring Harb. Perspect. Med. 2012; 2(5): a006940. https://doi.org/10.1101/cshperspect.a006940van Manen D., Rits M.A., Beugeling C., van Dort K., Schuitemaker H., Kootstra N.A. The effect of Trim5 polymorphisms on the clinical course of HIV-1 infection. PLoS Pathog. 2008; 4(2): e18. https://doi.org/10.1371/journal.ppat.0040018Kim K., Dauphin A., Komurlu S., McCauley S.M., Yurkovetskiy L., Carbone C., et al. Cyclophilin A protects HIV-1 from restriction by human TRIM5α. Nat. Microbiol. 2019; 4(12): 2044–51. https://doi.org/10.1038/s41564-019-0592-5Harris R.S., Hultquist J.F., Evans D.T. The restriction factors of human immunodeficiency virus. J. Biol. Chem. 2012; 287(49): 40875–83. https://doi.org/10.1074/jbc.r112.416925Engelman A., Cherepanov P. The lentiviral integrase binding protein LEDGF/p75 and HIV-1 replication. PLoS Pathog. 2008; 4(3): e1000046. https://doi.org/10.1371/journal.ppat.1000046Renzi G., Carta F., Supuran C.T. The integrase: an overview of a key player enzyme in the antiviral scenario. Int. J. Mol. Sci. 2023; 24(15): 12187. https://doi.org/10.3390/ijms241512187Lee M.S., Craigie R. A previously unidentified host protein protects retroviral DNA from autointegration. Proc. Natl Acad. Sci. USA. 1998; 95(4): 1528–33. https://doi.org/10.1073/pnas.95.4.1528Bin Hamid F., Kim J., Shin C.G. Cellular and viral determinants of retroviral nuclear entry. Can. J. Microbiol. 2016; 62(1): 1–15. https://doi.org/10.1139/cjm-2015-0350Tingey M., Li Y., Yu W., Young A., Yang W. Spelling out the roles of individual nucleoporins in nuclear export of mRNA. Nucleus. 2022; 13(1): 170–93. https://doi.org/10.1080/19491034.2022.2076965Endsley M.A., Somasunderam A.D., Li G., Oezguen N., Thiviyanathan V., Murray J.L., et al. Nuclear trafficking of the HIV-1 pre-integration complex depends on the ADAM10 intracellular domain. Virology. 2014; 454-455: 60–6. https://doi.org/10.1016/j.virol.2014.02.006Lee K., Ambrose Z., Martin T.D., Oztop I., Mulky A., Julias J.G., et al. Flexible use of nuclear import pathways by HIV-1. Cell Host Microbe. 2010; 7(3): 221–33. https://doi.org/10.1016/j.chom.2010.02.007Kane M., Yadav S.S., Bitzegeio J., Kutluay S.B., Zang T., Wilson S.J., et al. MX2 is an interferon-induced inhibitor of HIV-1 infection. Nature. 2013; 502(7472): 563–6. https://doi.org/10.1038/nature12653Wei W., Guo H., Ma M., Markham R., Yu X.F. Accumulation of MxB/Mx2-resistant HIV-1 capsid variants during expansion of the HIV-1 epidemic in human populations. EBioMedicine. 2016; 8: 230–6. https://doi.org/10.1016/j.ebiom.2016.04.020Lelek M., Casartelli N., Pellin D., et al. Chromatin organization at the nuclear pore favours HIV replication. Nat. Commun. 2015; 6: 6483. https://doi.org/10.1038/ncomms7483Demeulemeester J., De Rijck J., Gijsbers R., Debyser Z. Retroviral integration: Site matters: Mechanisms and consequences of retroviral integration site selection. Bioessays. 2015; 37(11): 1202–14. https://doi.org/10.1002/bies.201500051Bedwell G.J., Engelman A.N. Factors that mold the nuclear landscape of HIV-1 integration. Nucleic Acids Res. 2021; 49(2): 621–35. https://doi.org/10.1093/nar/gkaa1207Saito A., Henning M.S., Serrao E., Dubose B.N., Teng S., Huang J., et al. Capsid-CPSF6 interaction is dispensable for HIV-1 replication in primary cells but is selected during virus passage in vivo. J. Virol. 2016; 90(15): 6918–35. https://doi.org/10.1128/jvi.00019-16Maillot B., Lévy N., Eiler S., Crucifix C., Granger F., Richert L., et al. Structural and functional role of INI1 and LEDGF in the HIV-1 preintegration complex. PloS One. 2013; 8(4): e60734. https://doi.org/10.1371/journal.pone.0060734Lapaillerie D., Lelandais B., Mauro E., Lagadec F., Tumiotto C., Miskey C., et al. Modulation of the intrinsic chromatin binding property of HIV-1 integrase by LEDGF/p75. Nucleic Acids Res. 2021; 49(19): 11241–56. https://doi.org/10.1093/nar/gkab886Christ F., Voet A., Marchand A., Nicolet S., Desimmie B.A., Marchand D., et al. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat. Chem. Biol. 2010; 6(6): 442–8. https://doi.org/10.1038/nchembio.370Desimmie B.A., Schrijvers R., Demeulemeester J., Borrenberghs D., Weydert C., Thys W., et al. LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions. Retrovirology. 2013; 10: 57. https://doi.org/10.1186/1742-4690-10-57Le Rouzic E., Bonnard D., Chasset S., Bruneau J.M., Chevreuil F., Le Strat F., et al. Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage. Retrovirology. 2013; 10: 144. https://doi.org/10.1186/1742-4690-10-144Vranckx L.S., Demeulemeester J., Saleh S., Boll A., Vansant G., Schrijvers R., et al. LEDGIN-mediated inhibition of integrase-LEDGF/p75 interaction reduces reactivation of residual latent HIV. EBioMedicine. 2016; 8: 248–64. https://doi.org/10.1016/j.ebiom.2016.04.039Bruggemans A., Vansant G., Balakrishnan M., Mitchell M.L., Cai R., Christ F., et al. GS-9822, a preclinical LEDGIN candidate, displays a block-and-lock phenotype in cell culture. Antimicrob. Agents Chemother. 2023; 65(5): e02328-20. https://doi.org/10.1128/aac.02328-20Debyser Z., Bruggemans A., Van Belle S., Janssens J., Christ F. LEDGINs, inhibitors of the interaction between HIV-1 integrase and LEDGF/p75, are potent antivirals with a potential to cure HIV infection. Adv. Exp. Med. Biol. 2021;1322: 97–114. https://doi.org/10.1007/978-981-16-0267-2_4Romani B., Allahbakhshi E. Underlying mechanisms of HIV-1 latency. Virus Genes. 2017; 53(3): 329–39. https://doi.org/10.1007/s11262-017-1443-1Wang S., Qiu L., Yan X., Jin W., Wang Y., Chen L., et al. Loss of microRNA 122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G(1) -modulated P53 activity. Hepatology. 2012; 55(3): 730–41. https://doi.org/10.1002/hep.24809Bobkova M.R. HIV Latency [Latentnost’ VICh]. Moscow: Chelovek; 2021. (in Russian)Бобкова М.Р. Латентность ВИЧ. М.: Человек; 2021.Kuznetsova A.I., Gromov K.B., Kireev D.E., Shlykova A.V., Lopatukhin A.E., Kazennova E.V., et al. Analysis of Tat protein characteristics in human immunodeficiency virus type 1 sub-subtype A6 (Retroviridae: Orthoretrovirinae: Lentivirus: Human immunodeficiency virus-1). Voprosy virusologii. 2022; 66(6): 452–64. https://doi.org/10.36233/0507-4088-83Кузнецова А.И., Громов К.Б., Киреев Д.Е., Шлыкова А.В., Лопатухин А.Э., Казеннова Е.В. и др. Анализ особенностей белка Tat вируса иммунодефицита человека 1 типа суб-субтипа А6 (Retroviridae: Orthoretrovirinae: Lentivirus: Human immunodefciency virus-1). Вопросы вирусологии. 2021; 66(6): 452–64. https://doi.org/10.36233/0507-4088-83 https://elibrary.ru/cmzgyc (in Russian)Nchioua R., Bosso M., Kmiec D., Kirchhoff F. Cellular factors targeting HIV-1 transcription and viral RNA transcripts. Viruses. 2020; 12(5): 495. https://doi.org/10.3390/v12050495Mousseau G., Valente S.T. Role of host factors on the regulation of tat-mediated HIV-1 transcription. Curr. Pharm. Des. 2017; 23(28): 4079–90. https://doi.org/10.2174/1381612823666170622104355Naji S., Ambrus G., Cimermančič P., Reyes J.R., Johnson J.R., Filbrandt R., et al. Host cell interactome of HIV-1 Rev includes RNA helicases involved in multiple facets of virus production. Mol. Cell. Proteomics. 2012; 11(4): M111.015313. https://doi.org/10.1074/mcp.m111.015313Lerner G., Weaver N., Anokhin B., Spearman P. Advances in HIV-1 assembly. Viruses. 2022; 14(3): 478. https://doi.org/10.3390/v14030478Rose K.M. When in need of an ESCRT: The nature of virus assembly sites suggests mechanistic parallels between nuclear virus egress and retroviral budding. Viruses. 2021; 13(6): 1138. https://doi.org/10.3390/v13061138Sauter D. Counteraction of the multifunctional restriction factor tetherin. Front. Microbiol. 2014; 5: 163. https://doi.org/10.3389/fmicb.2014.00163McNatt M.W., Zang T., Bieniasz P.D. Vpu binds directly to tetherin and displaces it from nascent virions. PLoS Pathog. 2013; 9(4): e1003299. https://doi.org/10.1371/journal.ppat.1003299Pattishal K. Discovery and development of Zidovudine as the cornerstone of therapy to control human immunodeficiency virus infection. In: Adams J., Merluzzi V.J., eds. The Search for Antiviral Drugs: Case Histories from Concept to Clinic. Boston, MA: Birkhäuser; 1993.Drechsler H., Ayers C., Cutrell J., Maalouf N., Tebas P., Bedimo R. Current use of statins reduces risk of HIV rebound on suppressive HAART. PLoS One. 2017; 12(3): e0172175. https://doi.org/10.1371/journal.pone.0172175