Title |
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
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Published in |
Scientific Reports, May 2018
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DOI | 10.1038/s41598-018-26281-z |
Pubmed ID | |
Authors |
A. A. Latanova, S. Petkov, A. Kilpelainen, J. Jansons, O. E. Latyshev, Y. V. Kuzmenko, J. Hinkula, M. A. Abakumov, V. T. Valuev-Elliston, M. Gomelsky, V. L. Karpov, F. Chiodi, B. Wahren, D. Y. Logunov, E. S. Starodubova, M. G. Isaguliants |
Abstract |
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-γ 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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Unknown | 4 | 80% |
Demographic breakdown
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Science communicators (journalists, bloggers, editors) | 1 | 20% |
Mendeley readers
Geographical breakdown
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Unknown | 50 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 9 | 18% |
Student > Master | 7 | 14% |
Student > Ph. D. Student | 5 | 10% |
Other | 4 | 8% |
Student > Bachelor | 2 | 4% |
Other | 6 | 12% |
Unknown | 17 | 34% |
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Agricultural and Biological Sciences | 2 | 4% |
Other | 9 | 18% |
Unknown | 20 | 40% |