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Consensus Integrase of a New HIV-1 Genetic Variant CRF63_02A1

The high genetic variability of the human immunodeficiency virus (HIV-1) leads to a constant emergence of new genetic variants, including the recombinant virus CRF63_02A1, which is widespread in the Siberian Federal District of Russia. We studied HIV-1 CRF63_02A1 integrase (IN_CRF) catalyzing the in...

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Autores principales: Agapkina, Y. Y., Pustovarova, M. A., Korolev, S. P., Zyryanova, D. P., Ivlev, V. V., Totmenin, A. V., Gashnikova, N. M., Gottikh, M. B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: A.I. Gordeyev 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475865/
https://www.ncbi.nlm.nih.gov/pubmed/31024744
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author Agapkina, Y. Y.
Pustovarova, M. A.
Korolev, S. P.
Zyryanova, D. P.
Ivlev, V. V.
Totmenin, A. V.
Gashnikova, N. M.
Gottikh, M. B.
author_facet Agapkina, Y. Y.
Pustovarova, M. A.
Korolev, S. P.
Zyryanova, D. P.
Ivlev, V. V.
Totmenin, A. V.
Gashnikova, N. M.
Gottikh, M. B.
author_sort Agapkina, Y. Y.
collection PubMed
description The high genetic variability of the human immunodeficiency virus (HIV-1) leads to a constant emergence of new genetic variants, including the recombinant virus CRF63_02A1, which is widespread in the Siberian Federal District of Russia. We studied HIV-1 CRF63_02A1 integrase (IN_CRF) catalyzing the incorporation of viral DNA into the genome of an infected cell. The consensus sequence was designed, recombinant integrase was obtained, and its DNA-binding and catalytic activities were characterized. The stability of the IN_CRF complex with the DNA substrate did not differ from the complex stability for subtype A and B integrases; however, the rate of complex formation was significantly higher. The rates and efficiencies of 3’-processing and strand transfer reactions catalyzed by IN_CRF were found to be higher, too. Apparently, all these distinctive features of IN_CRF may result from specific amino acid substitutions in its N-terminal domain, which plays an important role in enzyme multimerization and binding to the DNA substrate. It was also found that the drug resistance mutations Q148K/G140S and G118R/E138K significantly reduce the catalytic activity of IN_CRF and its sensitivity to the strand transfer inhibitor raltegravir. Reduction in sensitivity to raltegravir was found to be much stronger in the case of double-mutation Q148K/G140S.
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spelling pubmed-64758652019-04-25 Consensus Integrase of a New HIV-1 Genetic Variant CRF63_02A1 Agapkina, Y. Y. Pustovarova, M. A. Korolev, S. P. Zyryanova, D. P. Ivlev, V. V. Totmenin, A. V. Gashnikova, N. M. Gottikh, M. B. Acta Naturae Research Article The high genetic variability of the human immunodeficiency virus (HIV-1) leads to a constant emergence of new genetic variants, including the recombinant virus CRF63_02A1, which is widespread in the Siberian Federal District of Russia. We studied HIV-1 CRF63_02A1 integrase (IN_CRF) catalyzing the incorporation of viral DNA into the genome of an infected cell. The consensus sequence was designed, recombinant integrase was obtained, and its DNA-binding and catalytic activities were characterized. The stability of the IN_CRF complex with the DNA substrate did not differ from the complex stability for subtype A and B integrases; however, the rate of complex formation was significantly higher. The rates and efficiencies of 3’-processing and strand transfer reactions catalyzed by IN_CRF were found to be higher, too. Apparently, all these distinctive features of IN_CRF may result from specific amino acid substitutions in its N-terminal domain, which plays an important role in enzyme multimerization and binding to the DNA substrate. It was also found that the drug resistance mutations Q148K/G140S and G118R/E138K significantly reduce the catalytic activity of IN_CRF and its sensitivity to the strand transfer inhibitor raltegravir. Reduction in sensitivity to raltegravir was found to be much stronger in the case of double-mutation Q148K/G140S. A.I. Gordeyev 2019 /pmc/articles/PMC6475865/ /pubmed/31024744 Text en Copyright ® 2019 National Research University Higher School of Economics. http://creativecommons.org/licenses/by/2.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Agapkina, Y. Y.
Pustovarova, M. A.
Korolev, S. P.
Zyryanova, D. P.
Ivlev, V. V.
Totmenin, A. V.
Gashnikova, N. M.
Gottikh, M. B.
Consensus Integrase of a New HIV-1 Genetic Variant CRF63_02A1
title Consensus Integrase of a New HIV-1 Genetic Variant CRF63_02A1
title_full Consensus Integrase of a New HIV-1 Genetic Variant CRF63_02A1
title_fullStr Consensus Integrase of a New HIV-1 Genetic Variant CRF63_02A1
title_full_unstemmed Consensus Integrase of a New HIV-1 Genetic Variant CRF63_02A1
title_short Consensus Integrase of a New HIV-1 Genetic Variant CRF63_02A1
title_sort consensus integrase of a new hiv-1 genetic variant crf63_02a1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475865/
https://www.ncbi.nlm.nih.gov/pubmed/31024744
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