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

Maria Isaguliants (Coresponding Author), 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 StarodubovaAnastasia Latanova

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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.

    Original languageEnglish
    Article number1219
    JournalMicroorganisms
    Volume9
    Issue number6
    DOIs
    Publication statusPublished - Jun 2021

    Keywords*

    • Antibodies
    • ART
    • HIV-1
    • Immunotoxicity
    • Integrase
    • Lentiviral transduction
    • Metastasis
    • Murine adenocarcinoma 4T1luc2 cells
    • Resistance to tumor growth
    • T-cell response
    • Therapeutic DNA vaccine
    • Tumor growth

    Field of Science*

    • 3.1 Basic medicine
    • 3.2 Clinical medicine
    • 1.6 Biological sciences

    Publication Type*

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

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