Problems of VirologyProblems of VirologyВопросы вирусологии0507-40882411-2097Central Research Institute for Epidemiology1673110.36233/0507-4088-305udlkybORIGINAL RESEARCHESОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯResearch ArticleNef HIV-1 (Retroviridae: Orthoretrovirinae: Lentivirus: Human immunodeficiency virus-1), multifunctional protein: features of genetic virus variants circulating in RussiaМультифункциональный белок Nef ВИЧ-1 (Retroviridae: Orthoretrovirinae: Lentivirus: Human immunodeficiency virus-1): особенности циркулирующих в России генетических вариантов вирусаhttps://orcid.org/0000-0001-5299-3081KuznetsovaAnna I.КузнецоваАнна Игоревна
Russian Federation

head of laboratory of T-lymphotropic viruses, PhD, leading researcher

канд. биол. наук, ведущий научный сотрудник, заведующая лабораторией вирусов лейкозов

a-myznikova@list.ruhttps://orcid.org/0000-0002-9180-9846AntonovaAnastasiia A.АнтоноваАнастасия Александровна
Russian Federation

PhD, Researcher, Laboratory of T-lymphotropic viruses

канд. биол. наук, научный сотрудник лаборатории вирусов лейкозов

anastaseika95@mail.ruhttps://orcid.org/0009-0001-0430-1578ProtasovaLarisa A.ПротасоваЛариса Анатольевна
Russian Federation

research assistant, Laboratory of T-lymphotropic viruses

лаборант-исследователь лаборатории вирусов лейкозов

larisa.protasova.03@mail.ruhttps://orcid.org/0000-0002-6352-2880GlyakinaAnna V.ГлякинаАнна Владимировна
Russian Federation

PhD, Researcher

канд. физ.-мат. наук, научный сотрудник

quark777a@gmail.comhttps://orcid.org/0000-0002-4150-2280KimKristina V.КимКристина Вячеславовна
Russian Federation

junior researcher, Laboratory of T-lymphotropic viruses

младший научных сотрудник лаборатории вирусов лейкозов

kimsya99@gmail.comhttps://orcid.org/0000-0002-4792-8928MunchakIana M.МунчакЯна Михайловна
Russian Federation

junior researcher, Laboratory of T-lymphotropic viruses

младший научный сотрудник лаборатории вирусов лейкозов

yana_munchak@mail.ruhttps://orcid.org/0000-0002-3110-0843MezhenskayaEkaterina N.МеженскаяЕкатерина Никитична
Russian Federation

PhD, Researcher, Laboratory of T-lymphotropic viruses

канд. биол. наук, научный сотрудник лаборатории вирусов лейкозов

belokopytova.01@mail.ruhttps://orcid.org/0000-0003-2495-6501Orlova-MorozovaElena A.Орлова-МорозоваЕлена Александровна
Russian Federation

PhD, Head of outpatient department

канд. мед. наук, заведующая амбулаторно-поликлиническим отделением

orlovamorozova@gmail.comhttps://orcid.org/0000-0001-9268-4929ProninAlexander Yu.ПронинАлександр Юрьевич
Russian Federation

PhD, Chief Physician

канд. мед. наук, главный врач

alexanderp909@gmail.comhttps://orcid.org/0000-0001-8755-1419PrilipovAlexey G.ПрилиповАлексей Геннадьевич
Russian Federation

Doctor of Biological Sciences, leading researcher, head of the laboratory of molecular genetics

д-р биол. наук, ведущий научный сотрудник, заведующий лабораторией молекулярной генетики

a_prilipov@mail.ruhttps://orcid.org/0000-0002-3962-1520GalzitskayaOxana V.ГалзитскаяОксана Валериановна
Russian Federation

Doctor of Physical and Mathematical Sciences, Head of the Bioinformatics Laboratory, Chief Researcher

д-р физ.-мат. наук, заведующая лабораторией биоинформатики, главный научный сотрудник

ogalzit@vega.protres.ruD.I. Ivanovsky Institute of Virology of National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. GamaleyaИнститут вирусологии им. Д.И. Ивановского ФГБУ «Национальный исследовательский центр эпидемиологии и микробиологии им. Н.Ф. Гамалеи» Минздрава РоссииInstitute of Mathematical Problems of Biology RAS – the Branch of Keldysh Institute of Applied Mathematics of Russian Academy of SciencesИнститут математических проблем биологии РАН – филиал ФГБУ «Федеральный исследовательский центр Институт прикладной математики им. М.В. Келдыша Российской академии наук»Center for the Prevention and Control of AIDS and Infectious DiseasesГБУЗ Московской области «Центр профилактики и борьбы со СПИД»Institute of Theoretical and Experimental Biophysics RASФБУН «Институт теоретической и экспериментальной биофизики» Российской академии наук3012202570651853526032025Copyright ©; 2025, Kuznetsova A.I., Antonova A.A., Protasova L.A., Glyakina A.V., Kim K.V., Munchak I.M., Mezhenskaya E.N., Orlova-Morozova E.A., Pronin A.Y., Prilipov A.G., Galzitskaya O.V.Copyright ©; 2025, Кузнецова А.И., Антонова А.А., Протасова Л.А., Глякина А.В., Ким К.В., Мунчак Я.М., Меженская Е.Н., Орлова-Морозова Е.А., Пронин А.Ю., Прилипов А.Г., Галзитская О.В.2025Kuznetsova A.I., Antonova A.A., Protasova L.A., Glyakina A.V., Kim K.V., Munchak I.M., Mezhenskaya E.N., Orlova-Morozova E.A., Pronin A.Y., Prilipov A.G., Galzitskaya O.V.Кузнецова А.И., Антонова А.А., Протасова Л.А., Глякина А.В., Ким К.В., Мунчак Я.М., Меженская Е.Н., Орлова-Морозова Е.А., Пронин А.Ю., Прилипов А.Г., Галзитская О.В.https://creativecommons.org/licenses/by/4.0https://virusjour.crie.ru/jour/article/view/16731

Introduction. Nef provides high level of HIV-1 replication due to synergy of its multiple functions and is an important factor in the pathogenesis of HIV infection. Nef is considered as a target for development of therapeutic agents. Mutations of drug resistance to dolutegravir can occur in Nef protein. Natural amino acid substitutions in Nef protein have been associated with the degree of progression of HIV infection, development of neurodegenerative and cardiovascular diseases in patients.

The aim of the study is to investigate Nef genetic diversity in HIV-1 variants circulating in Russia and in Moscow region.

Materials and methods. Total 216 Nef sequences obtained from whole blood samples of patients and 77 sequences downloaded from the Los Alamos International Database were analyzed. Consensus sequences of Nef sub-subtype A6, subtype B, CRF02_AG, CRF63_02A6, CRF133_A6B, and the reference sequence NL4-3 were compared. Genetic diversity of Nef sub-subtype A6 (Nef-A6) in patients with different stages of the disease was assessed. The presence of dolutegravir-associated drug resistance mutations in the Nef protein in HIV-1 variants circulating in Russia was also investigated.

Results. Differences in the spatial structures in consensus sequences of the studied HIV-1 variants were determined. It was shown that the conservatism of Nef-A6 in groups of patients with later stages of the disease was significantly higher. No mutations of drug resistance to dolutegravir were detected.

Conclusion. The differences in Nef sequences of HIV-1 variants circulating in Russia could affect the functional properties of the protein and could be taken into account in creating Nef-based therapies in the future. Obtained results indicate that there is no risk of resistance to dolutegravir associated with – mutations in the Nef protein. It outlines possible directions for further research into the genetic diversity of Nef.

Введение. Белок Nef обеспечивает высокий уровень репликации вируса иммунодефицита человека 1-го типа (ВИЧ-1) за счет синергии своих многочисленных функций, является важным фактором патогенеза ВИЧ-инфекции и рассматривается как мишень для разработки средств терапии. В белке Nef могут возникать мутации лекарственной устойчивости к долутегравиру. Природные аминокислотные замены в белке Nef ассоциированы со степенью прогрессирования ВИЧ-инфекции, развитием нейродегенеративных и сердечно-сосудистых заболеваний у пациентов.

Цель исследования – изучение генетического разнообразия Nef вариантов ВИЧ-1, циркулирующих в России и Московской области.

Материалы и методы. Проанализировано 216 последовательностей Nef, полученных из клинических образцов цельной крови пациентов, и 77 – выгруженных из Международной базы данных Лос-Аламос. Проведено сравнение консенсусных последовательностей Nef суб-субтипа А6, субтипа B, CRF02_AG, CRF63_02A6, CRF133_A6B и референсной последовательности NL4-3. Выполнена оценка генетического разнообразия Nef суб-субтипа А6 (Nef-A6) у пациентов с разными стадиями заболевания. Исследовано наличие мутаций лекарственной устойчивости к долутегравиру в белке Nef у вариантов ВИЧ-1, циркулирующих в России.

Результаты. Определены различия в пространственных структурах консенсусных последовательностей у исследуемых вариантов ВИЧ-1. Показано, что консервативность Nef-A6 в группах пациентов с более поздними стадиями заболевания была достоверно выше. Мутаций лекарственной устойчивости к долутегравиру обнаружено не было.

Заключение. Выявленные различия в последовательностях Nef у вариантов ВИЧ-1, циркулирующих в России, предположительно, могут оказывать влияние на функциональные свойства белка и учитываться при создании средств терапии на основе белка Nef в будущем. Полученные результаты свидетельствуют в пользу отсутствия рисков применения современных протоколов лечения ВИЧ-инфекции в России, связанных с мутациями лекарственной устойчивости к долутегравиру в белке Nef, и намечают возможные направления дальнейших исследований генетического разнообразия Nef.

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