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Fusion to Flaviviral Leader Peptide Targets HIV-1 Reverse Transcriptase for Secretion and Reduces Its Enzymatic Activity and Ability to Induce Oxidative Stress but Has No Major Effects on Its Immunogenic Performance in DNA-Immunized Mice
Russian Academic Science, Russia; Gamaleja Research Centre Epidemiol and Microbiol, Russia; Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
Russian Academic Science, Russia.
Karolinska Institute, Sweden.
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2017 (English)In: Journal of Immunology Research, ISSN 2314-8861, E-ISSN 2314-7156, article id 7407136Article in journal (Refereed) Published
Abstract [en]

Reverse transcriptase (RT) is a key enzyme in viral replication and susceptibility to ART and a crucial target of immunotherapy against drug-resistant HIV-1. RT induces oxidative stress which undermines the attempts to make it immunogenic. We hypothesized that artificial secretion may reduce the stress and make RT more immunogenic. Inactivated multidrug-resistant RT (RT1.14opt-in) was N-terminally fused to the signal providing secretion of NS1 protein of TBEV (Ld) generating optimized inactivated Ld-carrying enzyme RT1.14oil. Promotion of secretion prohibited proteasomal degradation increasing the half-life and content of RT1.14oil in cells and cell culture medium, drastically reduced the residual polymerase activity, and downmodulated oxidative stress. BALB/c mice were DNA-immunized with RT1.14opt-in or parental RT1.14oil by intradermal injections with electroporation. Fluorospot and ELISA tests revealed that RT1.14opt-in and RT1.14oil induced IFN-gamma/IL-2, RT1.14opt-in induced granzyme B, and RT1.14oil induced perforin production. Perforin secretion correlated with coproduction of IFN-gamma and IL-2 (R = 0,97). Both DNA immunogens induced strong anti-RT antibody response. Ld peptide was not immunogenic. Thus, Ld-driven secretion inferred little change to RT performance in DNA immunization. Positive outcome was the abrogation of polymerase activity increasing safety of RT-based DNA vaccines. Identification of the molecular determinants of low cellular immunogenicity of RT requires further studies.

Place, publisher, year, edition, pages
HINDAWI LTD , 2017. article id 7407136
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Other Clinical Medicine
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URN: urn:nbn:se:liu:diva-139656DOI: 10.1155/2017/7407136ISI: 000405393500001PubMedID: 28717654OAI: oai:DiVA.org:liu-139656DiVA, id: diva2:1133669
Note

Funding Agencies|Russian Foundation of Basic Research [14-04-01817]; Russian Science Foundation [15-15-30039]; EU Twinning Project VACTRAIN [692293]; Swedish Institute PI [19806_2016]

Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2017-09-04

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