Cellular Immune Response Induced by DNA Immunization of Mice with Drug Resistant Integrases of HIV-1 Clade A Offers Partial Protection against Growth and Metastatic Activity of Integrase-Expressing Adenocarcinoma Cells
Therapeutic DNA-vaccination against drug-resistant HIV-1 may hinder emergence and spread of drug-resistant HIV-1, allowing for longer successful antiretroviral treatment (ART) up-to relief of ART. We designed DNA-vaccines against drug-resistant HIV-1 based on consensus clade A integrase (IN) resista...
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MDPI AG
2021-06-01
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| Online Access: | https://www.mdpi.com/2076-2607/9/6/1219 |
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| author | Maria Isaguliants Olga Krotova Stefan Petkov Juris Jansons Ekaterina Bayurova Dzeina Mezale Ilze Fridrihsone Athina Kilpelainen Philip Podschwadt Yulia Agapkina Olga Smirnova Linda Kostic Mina Saleem Oleg Latyshev Olesja Eliseeva Anastasia Malkova Tatiana Gorodnicheva Britta Wahren Ilya Gordeychuk Elizaveta Starodubova Anastasia Latanova |
| author_facet | Maria Isaguliants Olga Krotova Stefan Petkov Juris Jansons Ekaterina Bayurova Dzeina Mezale Ilze Fridrihsone Athina Kilpelainen Philip Podschwadt Yulia Agapkina Olga Smirnova Linda Kostic Mina Saleem Oleg Latyshev Olesja Eliseeva Anastasia Malkova Tatiana Gorodnicheva Britta Wahren Ilya Gordeychuk Elizaveta Starodubova Anastasia Latanova |
| author_sort | Maria Isaguliants |
| collection | DOAJ |
| description | Therapeutic DNA-vaccination against drug-resistant HIV-1 may hinder emergence and spread of drug-resistant HIV-1, allowing for longer successful antiretroviral treatment (ART) up-to relief of ART. We designed DNA-vaccines against drug-resistant HIV-1 based on consensus clade A integrase (IN) resistant to raltegravir: IN_in_r1 (L74M/E92Q/V151I/N155H/G163R) or IN_in_r2 (E138K/G140S/Q148K) carrying D64V abrogating IN activity. INs, overexpressed in mammalian cells from synthetic genes, were assessed for stability, route of proteolytic degradation, and ability to induce oxidative stress. Both were found safe in immunotoxicity tests in mice, with no inherent carcinogenicity: their expression did not enhance tumorigenic or metastatic potential of adenocarcinoma 4T1 cells. DNA-immunization of mice with INs induced potent multicytokine T-cell response mainly against aa 209–239, and moderate IgG response cross-recognizing diverse IN variants. DNA-immunization with IN_in_r1 protected 60% of mice from challenge with 4Tlluc2 cells expressing non-mutated IN, while DNA-immunization with IN_in_r2 protected only 20% of mice, although tumor cells expressed IN matching the immunogen. Tumor size inversely correlated with IN-specific IFN-γ/IL-2 T-cell response. IN-expressing tumors displayed compromised metastatic activity restricted to lungs with reduced metastases size. Protective potential of IN immunogens relied on their immunogenicity for CD8+ T-cells, dependent on proteasomal processing and low level of oxidative stress. |
| first_indexed | 2024-03-10T10:42:21Z |
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| id | doaj.art-c917e04d846b4571aff6d1cd776891e0 |
| institution | Directory Open Access Journal |
| issn | 2076-2607 |
| language | English |
| last_indexed | 2024-03-10T10:42:21Z |
| publishDate | 2021-06-01 |
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| spelling | doaj.art-c917e04d846b4571aff6d1cd776891e02023-11-21T22:51:30ZengMDPI AGMicroorganisms2076-26072021-06-0196121910.3390/microorganisms9061219Cellular Immune Response Induced by DNA Immunization of Mice with Drug Resistant Integrases of HIV-1 Clade A Offers Partial Protection against Growth and Metastatic Activity of Integrase-Expressing Adenocarcinoma CellsMaria Isaguliants0Olga Krotova1Stefan Petkov2Juris Jansons3Ekaterina Bayurova4Dzeina Mezale5Ilze Fridrihsone6Athina Kilpelainen7Philip Podschwadt8Yulia Agapkina9Olga Smirnova10Linda Kostic11Mina Saleem12Oleg Latyshev13Olesja Eliseeva14Anastasia Malkova15Tatiana Gorodnicheva16Britta Wahren17Ilya Gordeychuk18Elizaveta Starodubova19Anastasia Latanova20Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, SwedenN.F. Gamaleya National Research Center for Epidemiology and Microbiology of the Ministry of Health of the Russian Federation, 123098 Moscow, RussiaDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, SwedenDepartment of Research, Riga Stradins University, LV-1007 Riga, LatviaN.F. Gamaleya National Research Center for Epidemiology and Microbiology of the Ministry of Health of the Russian Federation, 123098 Moscow, RussiaDepartment of Research, Riga Stradins University, LV-1007 Riga, LatviaDepartment of Research, Riga Stradins University, LV-1007 Riga, LatviaDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, SwedenDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, SwedenDepartment of Chemistry and Belozersky Institute of Physicochemical Biology, Moscow State University, 119991 Moscow, RussiaN.F. Gamaleya National Research Center for Epidemiology and Microbiology of the Ministry of Health of the Russian Federation, 123098 Moscow, RussiaDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, SwedenDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, SwedenN.F. Gamaleya National Research Center for Epidemiology and Microbiology of the Ministry of Health of the Russian Federation, 123098 Moscow, RussiaN.F. Gamaleya National Research Center for Epidemiology and Microbiology of the Ministry of Health of the Russian Federation, 123098 Moscow, RussiaInstitute of Medical Biological Research and Technologies, 143090 Krasnoznamensk, RussiaEvrogen, 117997 Moscow, RussiaDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, SwedenN.F. Gamaleya National Research Center for Epidemiology and Microbiology of the Ministry of Health of the Russian Federation, 123098 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaN.F. Gamaleya National Research Center for Epidemiology and Microbiology of the Ministry of Health of the Russian Federation, 123098 Moscow, RussiaTherapeutic DNA-vaccination against drug-resistant HIV-1 may hinder emergence and spread of drug-resistant HIV-1, allowing for longer successful antiretroviral treatment (ART) up-to relief of ART. We designed DNA-vaccines against drug-resistant HIV-1 based on consensus clade A integrase (IN) resistant to raltegravir: IN_in_r1 (L74M/E92Q/V151I/N155H/G163R) or IN_in_r2 (E138K/G140S/Q148K) carrying D64V abrogating IN activity. INs, overexpressed in mammalian cells from synthetic genes, were assessed for stability, route of proteolytic degradation, and ability to induce oxidative stress. Both were found safe in immunotoxicity tests in mice, with no inherent carcinogenicity: their expression did not enhance tumorigenic or metastatic potential of adenocarcinoma 4T1 cells. DNA-immunization of mice with INs induced potent multicytokine T-cell response mainly against aa 209–239, and moderate IgG response cross-recognizing diverse IN variants. DNA-immunization with IN_in_r1 protected 60% of mice from challenge with 4Tlluc2 cells expressing non-mutated IN, while DNA-immunization with IN_in_r2 protected only 20% of mice, although tumor cells expressed IN matching the immunogen. Tumor size inversely correlated with IN-specific IFN-γ/IL-2 T-cell response. IN-expressing tumors displayed compromised metastatic activity restricted to lungs with reduced metastases size. Protective potential of IN immunogens relied on their immunogenicity for CD8+ T-cells, dependent on proteasomal processing and low level of oxidative stress.https://www.mdpi.com/2076-2607/9/6/1219HIV-1ARTtherapeutic DNA vaccineintegraseimmunotoxicityT-cell response |
| spellingShingle | Maria Isaguliants Olga Krotova Stefan Petkov Juris Jansons Ekaterina Bayurova Dzeina Mezale Ilze Fridrihsone Athina Kilpelainen Philip Podschwadt Yulia Agapkina Olga Smirnova Linda Kostic Mina Saleem Oleg Latyshev Olesja Eliseeva Anastasia Malkova Tatiana Gorodnicheva Britta Wahren Ilya Gordeychuk Elizaveta Starodubova Anastasia Latanova Cellular Immune Response Induced by DNA Immunization of Mice with Drug Resistant Integrases of HIV-1 Clade A Offers Partial Protection against Growth and Metastatic Activity of Integrase-Expressing Adenocarcinoma Cells Microorganisms HIV-1 ART therapeutic DNA vaccine integrase immunotoxicity T-cell response |
| title | Cellular Immune Response Induced by DNA Immunization of Mice with Drug Resistant Integrases of HIV-1 Clade A Offers Partial Protection against Growth and Metastatic Activity of Integrase-Expressing Adenocarcinoma Cells |
| title_full | Cellular Immune Response Induced by DNA Immunization of Mice with Drug Resistant Integrases of HIV-1 Clade A Offers Partial Protection against Growth and Metastatic Activity of Integrase-Expressing Adenocarcinoma Cells |
| title_fullStr | Cellular Immune Response Induced by DNA Immunization of Mice with Drug Resistant Integrases of HIV-1 Clade A Offers Partial Protection against Growth and Metastatic Activity of Integrase-Expressing Adenocarcinoma Cells |
| title_full_unstemmed | Cellular Immune Response Induced by DNA Immunization of Mice with Drug Resistant Integrases of HIV-1 Clade A Offers Partial Protection against Growth and Metastatic Activity of Integrase-Expressing Adenocarcinoma Cells |
| title_short | Cellular Immune Response Induced by DNA Immunization of Mice with Drug Resistant Integrases of HIV-1 Clade A Offers Partial Protection against Growth and Metastatic Activity of Integrase-Expressing Adenocarcinoma Cells |
| title_sort | cellular immune response induced by dna immunization of mice with drug resistant integrases of hiv 1 clade a offers partial protection against growth and metastatic activity of integrase expressing adenocarcinoma cells |
| topic | HIV-1 ART therapeutic DNA vaccine integrase immunotoxicity T-cell response |
| url | https://www.mdpi.com/2076-2607/9/6/1219 |
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