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

Yulia Agapkina¹  Britta Wahren²  Mina Saleem²  Linda Kostic²  Stefan Petkov²  Athina Kilpelainen²  Maria Isaguliants²  Philip Podschwadt²  Ilze Fridrihsone³  Juris Jansons³  Dzeina Mezale³  Elizaveta Starodubova⁴  Tatiana Gorodnicheva⁵  Anastasia Malkova⁶  Olga Smirnova⁷  Olesja Eliseeva⁷  Ekaterina Bayurova⁷  Olga Krotova⁷  Ilya Gordeychuk⁷  Oleg Latyshev⁷  Anastasia Latanova⁷ 

[1] Department of Chemistry and Belozersky Institute of Physicochemical Biology, Moscow State University, 119991 Moscow, Russia;Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden;Department of Research, Riga Stradins University, LV-1007 Riga, Latvia;Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia;Evrogen, 117997 Moscow, Russia;Institute of Medical Biological Research and Technologies, 143090 Krasnoznamensk, Russia;N.F. Gamaleya National Research Center for Epidemiology and Microbiology of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia;

关键词: HIV-1;    ART;    therapeutic DNA vaccine;    integrase;    immunotoxicity;    T-cell response;   

DOI  :  10.3390/microorganisms9061219

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown