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

• Published in: Scientific reports Vol. 8; no. 1; pp. 8078 - 22
• Main Authors: Latanova, A. A., Petkov, S., Kilpelainen, A., Jansons, J., Latyshev, O. E., Kuzmenko, Y. V., Hinkula, J., Abakumov, M. A., Valuev-Elliston, V. T., Gomelsky, M., Karpov, V. L., Chiodi, F., Wahren, B., Logunov, D. Y., Starodubova, E. S., Isaguliants, M. G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.05.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/109; 13/21; 13/31; 13/44; 14/1; 14/5; 38; 38/1; 38/109; 38/22; 38/23; 38/44; 59; 59/5; 631/250/590/1991; 631/250/590/2291; 64; 64/60; 82; 82/1; 82/29; 82/80; 82/83; 96; 96/21; 96/31; 96/34; CD4 antigen; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA vaccines; Drug resistance; Electroporation; Epitopes; HIV; Human immunodeficiency virus; Humanities and Social Sciences; Immune response; Immunization; Immunogenicity; Lymphocytes T; Medicin och hälsovetenskap; multidisciplinary; Mutation; Polarity; RNA-directed DNA polymerase; Science; Science (multidisciplinary); Vaccines; γ-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-26281-z

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.