HIV-1 Protease as DNA Immunogen against Drug Resistance in HIV-1 Infection : DNA Immunization with Drug Resistant HIV-1 Protease Protects Mice from Challenge with Protease-Expressing Cells

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dc.contributor.authorPetkov, Stefan
dc.contributor.authorKilpeläinen, Athina
dc.contributor.authorBayurova, Ekaterina
dc.contributor.authorLatanova, Anastasia
dc.contributor.authorMezale, Dzeina
dc.contributor.authorFridrihsone, Ilse
dc.contributor.authorStarodubova, Elizaveta
dc.contributor.authorJansons, Juris
dc.contributor.authorDudorova, Alesja
dc.contributor.authorGordeychuk, Ilya
dc.contributor.authorWahren, Britta
dc.contributor.authorIsaguliants, Maria
dc.contributor.institutionResearch Department
dc.date.accessioned2024-02-27T06:40:01Z
dc.date.available2024-02-27T06:40:01Z
dc.date.issued2023-01
dc.descriptionPublisher Copyright: © 2022 by the authors.
dc.description.abstractDNA immunization with HIV-1 protease (PR) is advanced for immunotherapy of HIV-1 infection to reduce the number of infected cells producing drug-resistant virus. A consensus PR of the HIV-1 FSU_A strain was designed, expression-optimized, inactivated (D25N), and supplemented with drug resistance (DR) mutations M46I, I54V, and V82A common for FSU_A. PR variants with D25N/M46I/I54V (PR_Ai2mut) and with D25N/M46I/I54V/V82A (PR_Ai3mut) were cloned into the DNA vaccine vector pVAX1, and PR_Ai3mut, into a lentiviral vector for the transduction of murine mammary adenocarcinoma cells expressing luciferase 4T1luc2. BALB/c mice were DNA-immunized by intradermal injections of PR_Ai, PR_Ai2mut, PR_Ai3mut, vector pVAX1, or PBS with electroporation. All PR variants induced specific CD8+ T-cell responses revealed after splenocyte stimulation with PR-derived peptides. Splenocytes of mice DNA-immunized with PR_Ai and PR_Ai2mut were not activated by peptides carrying V82A, whereas splenocytes of PR_Ai3mut-immunized mice recognized both peptides with and without V82A mutation. Mutations M46I and I54V were immunologically silent. In the challenge study, DNA immunization with PR_Ai3mut protected mice from the outgrowth of subcutaneously implanted adenocarcinoma 4T1luc2 cells expressing PR_Ai3mut; a tumor was formed only in 1/10 implantation sites and no metastases were detected. Immunizations with other PR variants were not protective; all mice formed tumors and multiple metastasis in the lungs, liver, and spleen. CD8+ cells of PR_Ai3mut DNA-immunized mice exhibited strong IFN-γ/IL-2 responses against PR peptides, while the splenocytes of mice in other groups were nonresponsive. Thus, immunization with a DNA plasmid encoding inactive HIV-1 protease with DR mutations suppressed the growth and metastatic activity of tumor cells expressing PR identical to the one encoded by the immunogen. This demonstrates the capacity of T-cell response induced by DNA immunization to recognize single DR mutations, and supports the concept of the development of immunotherapies against drug resistance in HIV-1 infection. It also suggests that HIV-1-infected patients developing drug resistance may have a reduced natural immune response against DR HIV-1 mutations causing an immune escape.en
dc.description.statusPeer reviewed
dc.format.extent45
dc.format.extent8248680
dc.identifier.citationPetkov, S, Kilpeläinen, A, Bayurova, E, Latanova, A, Mezale, D, Fridrihsone, I, Starodubova, E, Jansons, J, Dudorova, A, Gordeychuk, I, Wahren, B & Isaguliants, M 2023, 'HIV-1 Protease as DNA Immunogen against Drug Resistance in HIV-1 Infection : DNA Immunization with Drug Resistant HIV-1 Protease Protects Mice from Challenge with Protease-Expressing Cells', Cancers, vol. 15, no. 1, 238, pp. 1-45. https://doi.org/10.3390/cancers15010238
dc.identifier.doi10.3390/cancers15010238
dc.identifier.issn2072-6694
dc.identifier.urihttps://dspace.rsu.lv/jspui/handle/123456789/15336
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=85146016708&partnerID=8YFLogxK
dc.language.isoeng
dc.relation.ispartofCancers
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectCD8+ T-cell response
dc.subjectDNA immunogen
dc.subjectdrug resistance
dc.subjectHIV-1
dc.subjectHIV-1-protein-expressing tumors
dc.subjectmammary gland adenocarcinoma 4T1luc2 cells
dc.subjectmetastatic activity
dc.subjectprotease
dc.subjectprotection from tumor challenge
dc.subjecttumor growth
dc.subject3.1 Basic medicine
dc.subject3.2 Clinical medicine
dc.subject1.1. Scientific article indexed in Web of Science and/or Scopus database
dc.subjectOncology
dc.subjectCancer Research
dc.subjectSDG 3 - Good Health and Well-being
dc.titleHIV-1 Protease as DNA Immunogen against Drug Resistance in HIV-1 Infection : DNA Immunization with Drug Resistant HIV-1 Protease Protects Mice from Challenge with Protease-Expressing Cellsen
dc.type/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article

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