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

Stefan Petkov, Athina Kilpeläinen, Ekaterina Bayurova, Anastasia Latanova, Dzeina Mezale, Ilse Fridrihsone, Elizaveta Starodubova, Juris Jansons, Alesja Dudorova, Ilya Gordeychuk, Britta Wahren, Maria Isaguliants (Coresponding Author)

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    3 Citations (Scopus)
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    Abstract

    DNA 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.

    Original languageEnglish
    Article number238
    Pages (from-to)1-45
    Number of pages45
    JournalCancers
    Volume15
    Issue number1
    DOIs
    Publication statusPublished - Jan 2023

    Keywords*

    • CD8+ T-cell response
    • DNA immunogen
    • drug resistance
    • HIV-1
    • HIV-1-protein-expressing tumors
    • mammary gland adenocarcinoma 4T1luc2 cells
    • metastatic activity
    • protease
    • protection from tumor challenge
    • tumor growth

    Field of Science*

    • 3.1 Basic medicine
    • 3.2 Clinical medicine

    Publication Type*

    • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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