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

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

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-resistan...

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Autores principales: 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
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Publicado: Nature Portfolio 2018
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spelling oai:doaj.org-article:1b38b6e3c64d4d089d2e1bc1520268482021-12-02T11:40:17ZCodon optimization and improved delivery/immunization regimen enhance the immune response against wild-type and drug-resistant HIV-1 reverse transcriptase, preserving its Th2-polarity10.1038/s41598-018-26281-z2045-2322https://doaj.org/article/1b38b6e3c64d4d089d2e1bc1520268482018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-26281-zhttps://doaj.org/toc/2045-2322Abstract 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.A. A. LatanovaS. PetkovA. KilpelainenJ. JansonsO. E. LatyshevY. V. KuzmenkoJ. HinkulaM. A. AbakumovV. T. Valuev-EllistonM. GomelskyV. L. KarpovF. ChiodiB. WahrenD. Y. LogunovE. S. StarodubovaM. G. IsaguliantsNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-22 (2018)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
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
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
description 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.
format article
author 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
author_facet 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
author_sort A. A. Latanova
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
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
publisher Nature Portfolio
publishDate 2018
url https://doaj.org/article/1b38b6e3c64d4d089d2e1bc152026848
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