Problems of VirologyProblems of VirologyВопросы вирусологии0507-40882411-2097Central Research Institute for Epidemiology62910.36233/0507-4088-124REVIEWSОБЗОРЫResearch ArticleThe prospects for the use of drugs based on the phenomenon of RNA interference against HIV infectionПерспектива применения препаратов на основе явления РНК-интерференции против ВИЧ-инфекцииhttps://orcid.org/0000-0002-5682-4581PashkovEvgenij A.ПашковЕвгений Алексеевич
Russian Federation

Junior Researcher of Federal State Budgetary Scientific Institution “I. Mechnikov Research Institute of Vaccines and Sera”

младший научный сотрудник «Научно-исследовательский институт вакцин и сывороток имени И.И. Мечникова» Минобрнауки России

pashckov.j@yandex.ruhttps://orcid.org/0000-0003-4295-7858PakAnastasia V.ПакАнастасия В.
Russian Federation
pashckov.j@yandex.ruhttps://orcid.org/0000-0002-4963-5053PashkovEvgenij P.ПашковЕвгений П.
Russian Federation
pashckov.j@yandex.ruhttps://orcid.org/0000-0002-8099-6201BykovAnatoliy S.БыковАнатолий С.
Russian Federation
pashckov.j@yandex.ruBudanovaElena V.БудановаЕлена В.
Russian Federation
pashckov.j@yandex.ruhttps://orcid.org/0000-0001-8962-4765PoddubikovAlexander V.ПоддубиковАлександр В.
Russian Federation
pashckov.j@yandex.ruhttps://orcid.org/0000-0003-1757-8389SvitichOxana A.СвитичОксана А.
Russian Federation
pashckov.j@yandex.ruhttps://orcid.org/0000-0002-0017-1892ZverevVitaly V.ЗверевВиталий В.
Russian Federation
pashckov.j@yandex.ruI.M. Sechenov First Moscow State Medical University (Sechenov University)ФГАОУ ВО «Первый Московский государственный медицинский университет имени И.М. Сеченова» Минздрава России (Сеченовский Университет)Federal State Budgetary Scientific Institution “I. Mechnikov Research Institute of Vaccines and Sera”ФГБНУ «Научно-исследовательский институт вакцин и сывороток имени И.И. Мечникова» Минобрнауки России1611202267427828925082022Copyright ©; 2022, Pashkov E.A., Pak A.V., Pashkov E.P., Bykov A.S., Budanova E.V., Poddubikov A.V., Svitich O.A., Zverev V.V.Copyright ©; 2022, Пашков Е.А., Пак А.В., Пашков Е.П., Быков А.С., Буданова Е.В., Поддубиков А.В., Свитич О.А., Зверев В.В.2022Pashkov E.A., Pak A.V., Pashkov E.P., Bykov A.S., Budanova E.V., Poddubikov A.V., Svitich O.A., Zverev V.V.Пашков Е.А., Пак А.В., Пашков Е.П., Быков А.С., Буданова Е.В., Поддубиков А.В., Свитич О.А., Зверев В.В.https://creativecommons.org/licenses/by/4.0https://virusjour.crie.ru/jour/article/view/629

The human immunodeficiency virus (HIV) is currently one of the most pressing global health problems. Since its discovery in 1978, HIV has claimed the lives of more than 35 million people, and the number of people infected today reaches 37 million. In the absence of highly active antiretroviral therapy (HAART), HIV infection is characterized by a steady decrease in the number of CD4+ T-lymphocytes, but its manifestations can affect the central nervous, cardiovascular, digestive, endocrine and genitourinary systems. At the same time, complications induced by representatives of pathogenic and opportunistic microflora, which can lead to the development of bacterial, fungal and viral concomitant infections, are of particular danger. It should be borne in mind that an important problem is the emergence of viruses resistant to standard therapy, as well as the toxicity of the drugs themselves for the body. In the context of this review, of particular interest is the assessment of the prospects for the creation and clinical use of drugs based on small interfering RNAs aimed at suppressing the reproduction of HIV, taking into account the experience of similar studies conducted earlier. RNA interference is a cascade of regulatory reactions in eukaryotic cells, which results in the degradation of foreign messenger RNA. The development of drugs based on the mechanism of RNA interference will overcome the problem of viral resistance. Along with this, this technology makes it possible to quickly respond to outbreaks of new viral diseases.

На сегодняшний день вирус иммунодефицита человека (ВИЧ, HIV) является одной из наиболее актуальных проблем мирового здравоохранения. С момента открытия в 1978 г. он унёс жизни более 35 млн человек, а число инфицированных сегодня достигает 37 млн человек. При отсутствии высокоактивной антиретровирусной терапии ВИЧ-инфекция характеризуется неуклонным снижением количества CD4+ Т-лимфоцитов, однако её проявления способны затронуть центральную нервную, сердечно-сосудистую, пищеварительную, эндокринную и мочеполовую системы. Одновременно с этим особую опасность представляют осложнения, индуцированные представителями патогенной и условно-патогенной микрофлоры, которые могут привести к развитию сопутствующих бактериальных, грибковых и вирусных инфекций. Следует учитывать, что важной проблемой является возникновение вирусов, устойчивых к традиционным лекарственным препаратам, а также токсичность самих лекарственных средств для организма. В контексте настоящего обзора особый интерес представляет оценка перспективности создания и клинического применения препаратов на основе малых интерферирующих РНК, направленных на подавление репродукции ВИЧ, с учётом опыта подобных исследований, проведённых ранее. РНК-интерференция – каскад регуляторных реакций в эукариотических клетках, в результате которого происходит деградация чужеродной матричной РНК. Разработка препаратов на основе механизма РНК-интерференции позволит преодолеть проблему вирусной резистентности. Наряду с этим данная технология позволяет оперативно реагировать на случаи возникновения вспышек новых вирусных заболеваний.

HIV-1HIVsmall interfering RNAgene knockdownreviewdrug resistanceВИЧ-1HIVмалые интерферирующие РНКнокаут генаобзорлекарственная резистентностьМинистерство образования и науки РоссииMinistry of Education and Science of Russia075-15-2021-676WHO. Fact sheet. HIV. Available at: https://www.who.int/news-room/fact-sheets/detail/hiv-aidsВОЗ. Информационный бюллетень. ВИЧ. Available at: https://www.who.int/ru/news-room/fact-sheets/detail/hiv-aidsInternational Committee on Taxonomy of Viruses. Current ICTV Taxonomy Release. Taxonomy Browser. Available at: https://talk.ictvonline.org/taxonomyNyamweya S., Hegedus A., Jaye A., Rowland-Jones S., Flanagan K.L., Macallan D.C. Comparing HIV-1 and HIV-2 infection: Lessons for viral immunopathogenesis. Rev. Med. Virol. 2013; 23(4): 221–40. https://doi.org/10.1002/rmv.1739Spudich S.S., Ances B.M. Neurologic complications of HIV infection. Top. Antivir. Med. 2012; 20(2): 41–7.Vachiat A., McCutcheon K., Tsabedze N., Zachariah D., Manga P. HIV and ischemic heart disease. J. Am. Coll. Cardiol. 2017; 69(1): 73–82. https://doi.org/10.1016/j.jacc.2016.09.979Kearns A., Gordon J., Burdo T.H., Qin X. HIV-1-associated atherosclerosis: unraveling the missing link. J. Am. Coll. Cardiol. 2017; 69(25): 3084–98. https://doi.org/10.1016/j.jacc.2017.05.012.Ances B.M., Anderson A.M., Letendre S.L. CROI 2021: Neurologic complications of HIV-1 infection or COVID-19. Top. Antivir. Med. 2021; 29(2): 334–43.Heyns C.F., Groeneveld A.E., Sigarroa N.B. Urologic complications of HIV and AIDS. Nat. Clin. Pract. Urol. 2009; 6(1): 32–43. https://doi.org/10.1038/ncpuro1273Sim J.H., Mukerji S.S., Russo S.C., Lo J. Gastrointestinal dysfunction and HIV comorbidities. Curr. HIV/AIDS Rep. 2021; 18(1): 57–62. https://doi.org/10.1007/s11904-020-00537-8Barbier F., Mer M., Szychowiak P., Miller R.F., Mariotte É., Galicier L., et al. Management of HIV-infected patients in the intensive care unit. Intensive Care Med. 2020; 46(2): 329–42. https://doi.org/10.1007/s00134-020-05945-3Limper A.H., Adenis A., Le T., Harrison T.S. Fungal infections in HIV/AIDS. Lancet Infect. Dis. 2017; 17(11): e334–43. https://doi.org/10.1016/S1473-3099(17)30303-1José R.J., Periselneris J.N., Brown J.S. Opportunistic bacterial, viral and fungal infections of the lung. Medicine (Abingdon). 2020; 48(6): 366–72. https://doi.org/10.1016/j.mpmed.2020.03.006Wielgos A.A., Pietrzak B. Human papilloma virus-related premalignant and malignant lesions of the cervix and anogenital tract in immunocompromised women. Ginekol. Pol. 2020; 91(1): 32–7. https://doi.org/10.5603/GP.2020.0008Cesarman E., Damania B., Krown S.E., Martin J., Bower M., Whitby D. Kaposi sarcoma. Nat. Rev. Dis. Primers. 2019; 5(1): 9. https://doi.org/10.1038/s41572-019-0060-9.Thandra K.C., Barsouk A., Saginala K., Padala S.A., Barsouk A., Rawla P. Epidemiology of non-Hodgkin’s lymphoma. Med. Sci. (Basel). 2021; 9(1): 5. https://doi.org/10.3390/medsci9010005Abram M.E., Ferris A.L., Shao W., Alvord W.G., Hughes S.H. Nature, position, and frequency of mutations made in a single cycle of HIV-1 replication. J. Virol. 2010; 84(19): 9864–78. https://doi.org/10.1128/JVI.00915-10Margolis A.M., Heverling H., Pham P.A., Stolbach A. A review of the toxicity of HIV medications. J. Med. Toxicol. 2014; 10(1): 26–39. https://doi.org/10.1007/s13181-013-0325-8Clutter D.S., Jordan M.R., Bertagnolio S., Shafer R.W. HIV-1 drug resistance and resistance testing. Infect. Genet. Evol. 2016; 46: 292–307. https://doi.org/10.1016/j.meegid.2016.08.031Kachanov D.A., Atangulov G.I., Khamade Kh., Lishkevich I.A., Elshashtiri M.N.D., Ivanyan Zh.N., et al. Aspects of the prescribing antiretroviral drugs in the treatment of HIV-infected patients. Mezhdunarodnyy nauchno-issledovatel’skiy zhurnal. 2021; (2-3): 25–30. https://doi.org/10.23670/IRJ.2021.103.2.066 (in Russian)Качанов Д.А., Атангулов Г.И., Хамаде Х., Лишкевич И.А., Елшаштири М.Н.Д., Иванян Ж.Н. и др. Особенности назначения антиретровирусных препаратов при лечении ВИЧ-инфицированных пациентов. Международный научно-исследовательский журнал. 2021; (2-3): 25–30. https://doi.org/10.23670/IRJ.2021.103.2.066EPIVIR (lamivudine). Tablets and Oral Solution. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020564s031,020596s030lbl.pdfJohnson M.A., Verpooten G.A., Daniel M.J., Plumb R., Moss J., Van Caesbroeck D., et al. Single dose pharmacokinetics of lamivudine in subjects with impaired renal function and the effect of haemodialysis. Br. J. Clin. Pharmacol. 1998; 46(1): 21–7. https://doi.org/10.1046/j.1365-2125.1998.00044.xManfredi R., Calza L. HIV infection and the pancreas: risk factors and potential management guidelines. Int. J. STD AIDS. 2008; 19(2): 99–105. https://doi.org/10.1258/ijsa.2007.007076Herlitz L.C., Mohan S., Stokes M.B., Radhakrishnan J., D’Agati V.D., Markowitz G.S. Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities. Kidney Int. 2010; 78(11): 1171–7. https://doi.org/10.1038/ki.2010.318Abe K., Obara T., Kamio S., Kondo A., Imamura J., Goto T., et al. Renal function in Japanese HIV-1-positive patients who switch to tenofovir alafenamide fumarate after long-term tenofovir disoproxil fumarate: a single-center observational study. AIDS Res. Ther. 2021; 18(1): 94. https://doi.org/10.1186/s12981-021-00420-5Wessman M., Weis N., Katzenstein T.L., Lebech A.M., Thorsteinsson K., Hansen A.E., et al. The significance of HIV to bone mineral density. Ugeskr. Laeger. 2017; 179(36): V05170420. (in Danish)Ruane P.J., DeJesus E., Berger D., Markowitz M., Bredeek U.F., Callebaut C., et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J. Acquir. Immune Defic. Syndr. 2013; 63(4): 449–55. https://doi.org/10.1097/QAI.0b013e3182965d45Bañó M., Morén C., Barroso S., Juárez D.L., Guitart-Mampel M., González-Casacuberta I., et al. Mitochondrial toxicogenomics for antiretroviral management: HIV post-exposure prophylaxis in uninfected patients. Front. Genet. 2020; 11: 497. https://doi.org/10.3389/fgene.2020.00497Kinloch-De Loës S., Hirschel B.J., Hoen B., Cooper D.A., Tindall B., Carr A., et al. A controlled trial of zidovudine in primary human immunodeficiency virus infection. N. Engl. J. Med. 1995; 333(7): 408–13. https://doi.org/10.1056/NEJM199508173330702Hachiya A., Kodama E.N., Schuckmann M.M., Kirby K.A., Michailidis E., Sakagami Y., et al. K70Q adds high-level tenofovir resistance to “Q151M complex” HIV reverse transcriptase through the enhanced discrimination mechanism. PLoS One. 2011; 6(1): e16242. https://doi.org/10.1371/journal.pone.0016242Sarafianos S.G., Das K., Clark A.D.Jr., Ding J., Boyer P.L., Hughes S.H., et al. Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids. Proc. Natl Acad. Sci. USA. 1999; 96(18): 10027–32. https://doi.org/10.1073/pnas.96.18.10027Marcelin A.G. Resistance to nucleoside reverse transcriptase inhibitors. In: Geretti A.M., ed. Antiretroviral Resistance in Clinical Practice. Chapter 1. London: Mediscript; 2006.Rai M.A., Pannek S., Fichtenbaum C.J. Emerging reverse transcriptase inhibitors for HIV-1 infection. Expert. Opin. Emerg. Drugs. 2018; 23(2): 149–57. https://doi.org/10.1080/14728214.2018.1474202Rihs T.A., Begley K., Smith D.E., Sarangapany J., Callaghan A., Kelly M., et al. Efavirenz and chronic neuropsychiatric symptoms: a cross-sectional case control study. HIV Med. 2006; 7(8): 544–8. https://doi.org/10.1111/j.1468-1293.2006.00419.xMollan K.R., Smurzynski M., Eron J.J., Daar E.S., Campbell T.B., Sax P.E., et al. Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Ann. Intern. Med. 2014; 161(1): 1–10. https://doi.org/10.7326/M14-0293Leutscher P.D., Stecher C., Storgaard M., Larsen C.S. Discontinuation of efavirenz therapy in HIV patients due to neuropsychiatric adverse effects. Scand. J. Infect. Dis. 2013; 45(8): 645–51. https://doi.org/10.3109/00365548.2013.773067Cohen C., Wohl D., Arribas J.R., Henry K., Van Lunzen J., Bloch M., et al. Week 48 results from a randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults. AIDS. 2014; 28(7): 989–97. https://doi.org/10.1097/QAD.0000000000000169Hsiou Y., Das K., Ding J., Clark A.D.Jr., Kleim J.P., Rösner M., et al. Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance. J. Mol. Biol. 1998; 284(2): 313–23. https://doi.org/10.1006/jmbi.1998.2171Kertesz D.J., Brotherton-Pleiss C., Yang M., Wang Z., Lin X., Qiu Z., et al. Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-benzyl derivatives with broad potency against resistant mutant viruses. Bioorg. Med. Chem. Lett. 2010; 20(14): 4215–8. https://doi.org/10.1016/j.bmcl.2010.05.040Betancor G., Álvarez M., Marcelli B., Andrés C., Martínez M.A., Menéndez-Arias L. Effects of HIV-1 reverse transcriptase connection subdomain mutations on polypurine tract removal and initiation of (+)-strand DNA synthesis. Nucleic. Acids. Res. 2015; 43(4): 2259–70. https://doi.org/10.1093/nar/gkv077Kotler D.P. HIV and antiretroviral therapy: lipid abnormalities and associated cardiovascular risk in HIV-infected patients. J. Acquir. Immune Defic. Syndr. 2008; 49(Suppl. 2): S79–85. https://doi.org/10.1097/QAI.0b013e318186519cVyas A.K., Koster J.C., Tzekov A., Hruz P.W. Effects of the HIV protease inhibitor ritonavir on GLUT4 knock-out mice. J. Biol. Chem. 2010; 285(47): 36395–400. https://doi.org/10.1074/jbc.M110.176321Hardy W.D., Gulick R.M., Mayer H., Fätkenheuer G., Nelson M., Heera J., et al. Two-year safety and virologic efficacy of maraviroc in treatment-experienced patients with CCR5-tropic HIV-1 infection: 96-week combined analysis of MOTIVATE 1 and 2. J. Acquir. Immune Defic. Syndr. 2010; 55(5): 558–64. https://doi.org/10.1097/QAI.0b013e3181ee3d82Yuen M.F., Schiefke I., Yoon J.H., Ahn S.H., Heo J., Kim J.H., et al. RNA interference therapy with ARC-520 results in prolonged hepatitis B surface antigen response in patients with chronic hepatitis B infection. Hepatology. 2020; 72(1): 19–31. https://doi.org/10.1002/hep.31008.Janssen H.L., Reesink H.W., Lawitz E.J., Zeuzem S., RodriguezTorres M., Patel K., et al. Treatment of HCV infection by targeting microRNA. N. Engl. J. Med. 2013; 368(18): 1685–94. https://doi.org/10.1056/nejmoa1209026Qureshi A., Tantray V.G., Kirmani A.R., Ahangar A.G. A review on current status of antiviral siRNA. Rev. Med. Virol. 2018; 28(4): e1976. https://doi.org/10.1002/rmv.1976Pashkov E.A., Fayzuloev E.B., Svitich O.A., Sergeev O.V., Zverev V.V. The potential of synthetic small interfering RNA-based antiviral drugs for influenza treatment. Voprosy virusologii. 2020; 65(4): 182–90. https://doi.org/10.36233/0507-4088-2020-65-4-182-190 (in Russian)Пашков Е.А., Файзулоев Е.Б., Свитич О.А., Сергеев О.В., Зверев В.В. Перспектива создания специфических противогриппозных препаратов на основе синтетических малых интерферирующих РНК. Вопросы вирусологии. 2020; 65(4): 182–90. https://doi.org/10.36233/0507-4088-2020-65-4-182-190Page K.A., Liegler T., Feinberg M.B. Use of a green fluorescent protein as a marker for human immunodeficiency virus type 1 infection. AIDS Res. Hum. Retroviruses. 1997 Sep 1;13(13):1077-81. https://doi.org/10.1089/aid.1997.13.1077.Novina C.D., Murray M.F., Dykxhoorn D.M., Beresford P.J., Riess J., Lee S.K., et al. siRNA-directed inhibition of HIV-1 infection. Nat. Med. 2002; 8(7): 681–6. https://doi.org/10.1038/nm725Coburn G.A., Cullen B.R. Potent and specific inhibition of human immunodeficiency virus type 1 replication by RNA interference. J. Virol. 2002; 76(18): 9225–31. https://doi.org/10.1128/jvi.76.18.9225-9231.2002Hayafune M., Miyano-Kurosaki N., Park W.S., Moori Y., Takaku H. Silencing of HIV-1 gene expression by two types of siRNA expression systems. Antivir. Chem. Chemother. 2006; 17(5): 241–9. https://doi.org/10.1177/095632020601700501Kretova O.V., Fedoseeva D.M., Gorbacheva M.A., Gashnikova N.M., Gashnikova M.P., Melnikova N.V., et al. Six highly conserved targets of RNAi revealed in HIV-1-infected patients from Russia are also present in many HIV-1 strains worldwide. Mol. Ther. Nucleic. Acids. 2017; 8: 330–44. https://doi.org/10.1016/j.omtn.2017.07.010Aquaro S., Caliò R., Balzarini J., Bellocchi M.C., Garaci E., Perno C.F. Macrophages and HIV infection: therapeutical approaches toward this strategic virus reservoir. Antiviral. Res. 2002; 55(2): 209–25. https://doi.org/10.1016/s0166-3542(02)00052-9Trillo-Pazos G., Diamanturos A., Rislove L., Menza T., Chao W., Belem P., et al. Detection of HIV-1 DNA in microglia/macrophages, astrocytes and neurons isolated from brain tissue with HIV-1 encephalitis by laser capture microdissection. Brain Pathol. 2003; 13(2): 144–54. https://doi.org/10.1111/j.1750-3639.2003.tb00014.xDave R.S., Pomerantz R.J. Antiviral effects of human immunodeficiency virus type 1-specific small interfering RNAs against targets conserved in select neurotropic viral strains. J. Virol. 2004; 78(24): 13687–96. https://doi.org/10.1128/JVI.78.24.13687-13696.2004Lesch M., Luckner M., Meyer M., Weege F., Gravenstein I., Raftery M., et al. RNAi-based small molecule repositioning reveals clinically approved urea-based kinase inhibitors as broadly active antivirals. PLoS Pathog. 2019; 15(3): e1007601. https://doi.org/10.1371/journal.ppat.1007601Brass 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.1152725Rodriguez M., Lapierre J., Ojha C.R., Kaushik A., Batrakova E., Kashanchi F., et al. Intranasal drug delivery of small interfering RNA targeting Beclin1 encapsulated with polyethylenimine (PEI) in mouse brain to achieve HIV attenuation. Sci. Rep. 2017; 7(1): 1862. https://doi.org/10.1038/s41598-017-01819-9Capranico G., Tinelli S., Austin C.A., Fisher M.L., Zunino F. Different patterns of gene expression of topoisomerase II isoforms in differentiated tissues during murine development. Biochim. Biophys. Acta. 1992; 1132(1): 43–8. https://doi.org/10.1016/0167-4781(92)90050-aSunnam L.B.K., Kondapi A.K. Topoisomerase II β gene specific siRNA delivery by nanoparticles prepared with c-ter Apotransferrin and its effect on HIV-1 replication. Mol. Biotechnol. 2021; 63(8): 732–45. https://doi.org/10.1007/s12033-021-00334-7Wheeler L.A., Vrbanac V., Trifonova R., Brehm M.A., Gilboa-Geffen A., Tanno S., et al. Durable knockdown and protection from HIV transmission in humanized mice treated with gel-formulated CD4 aptamer-siRNA chimeras. Mol. Ther. 2013; 21(7): 1378–89. https://doi.org/10.1038/mt.2013.77