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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
Russian Acad Sci, Russia; Karolinska Inst, Sweden; Gamaleja Res Ctr Epidemiol and Microbiol, Russia.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
Riga Stradins Univ, Latvia.
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8078Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2018. Vol. 8, article id 8078
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Microbiology in the medical area
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URN: urn:nbn:se:liu:diva-148383DOI: 10.1038/s41598-018-26281-zISI: 000432928200003PubMedID: 29799015OAI: oai:DiVA.org:liu-148383DiVA, id: diva2:1218966
Note

Funding Agencies|Russian Fund for Basic Research [17-54-30002]; RAS Presidium Program "Molecular and cell biology and post-genome technologies" [01201456591]; Russian Science Foundation [15-15-30039]; EU Twinning project VACTRAIN [692293]; PI project of the Swedish Institute [19806_2016 INNOVIMMUNE]; VACTRAIN [692293]; INNOVIMMUNE; Ministry of Education and Science of the Russian Federation [K2-2016-069]

Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2018-07-03

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