Codon optimization and improved delivery/immunization regimen enhance the immune response against wild-type and drug-resistant HIV-1 reverse transcriptase, preserving its Th2-polarity

被引:19
|
作者
Latanova, A. A. [1 ,2 ,3 ]
Petkov, S. [2 ]
Kilpelainen, A. [2 ]
Jansons, J. [5 ]
Latyshev, O. E. [3 ,4 ]
Kuzmenko, Y. V. [1 ]
Hinkula, J. [2 ,6 ]
Abakumov, M. A. [7 ,8 ]
Valuev-Elliston, V. T. [1 ]
Gomelsky, M. [9 ]
Karpov, V. L. [1 ]
Chiodi, F. [2 ]
Wahren, B. [2 ]
Logunov, D. Y. [3 ,4 ]
Starodubova, E. S. [1 ,4 ]
Isaguliants, M. G. [3 ,4 ,5 ]
机构
[1] Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow, Russia
[2] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden
[3] Gamaleja Res Ctr Epidemiol & Microbiol, Moscow, Russia
[4] Russian Acad Sci, Chumakov Fed Sci Ctr Res & Dev Immune & Biol Prod, Moscow, Russia
[5] Riga Stradins Univ, Riga, Latvia
[6] Linkoping Univ, Linkoping, Sweden
[7] Pirogov Russian Natl Res Med Univ, Minist Hlth Russian Federat, Res & Educ Ctr Med Nanobiotechnol, Moscow, Russia
[8] Natl Univ Sci & Technol MISIS, Moscow, Russia
[9] Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA
来源
SCIENTIFIC REPORTS | 2018年 / 8卷
基金
俄罗斯科学基金会;
关键词
DNA VACCINE DELIVERY; C-DI-GMP; T-CELLS; PROTEASOMAL DEGRADATION; PLASMODIUM-FALCIPARUM; ANTIBODY-RESPONSE; HUMORAL IMMUNITY; IN-VITRO; VIRUS; IMMUNOGENICITY;
D O I
10.1038/s41598-018-26281-z
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
DNA vaccines require a considerable enhancement of immunogenicity. Here, we optimized a prototype DNA vaccine against drug-resistant HIV-1 based on a weak Th2-immunogen, HIV-1 reverse transcriptase (RT). We designed expression-optimized genes encoding inactivated wild-type and drug-resistant RTs (RT-DNAs) and introduced them into mice by intradermal injections followed by electroporation. RT-DNAs were administered as single or double primes with or without cyclic-di-GMP, or as a prime followed by boost with RT-DNA mixed with a luciferase-encoding plasmid ("surrogate challenge"). Repeated primes improved cellular responses and broadened epitope specificity. Addition of cyclic-di-GMP induced a transient increase in IFN-gamma production. The strongest anti-RT immune response was achieved in a prime-boost protocol with electroporation by short 100V pulses done using penetrating electrodes. The RT-specific response, dominated by CD4+T-cells, targeted epitopes at aa 199-220 and aa 528-543. Drug-resistance mutations disrupted the epitope at aa 205-220, while the CTL epitope at aa 202-210 was not affected. Overall, multiparametric optimization of RT strengthened its Th2- performance. A rapid loss of RT/luciferase-expressing cells in the surrogate challenge experiment revealed a lytic potential of anti-RT response. Such lytic CD4+ response would be beneficial for an HIV vaccine due to its comparative insensitivity to immune escape.
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页数:22
相关论文
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