Abstract
Experimental increase of CpG dinucleotides in an RNA virus genome impairs infection providing a promising approach for vaccine development. While CpG recoding is an emerging and promising vaccine approach, little is known about infection phenotypes caused by recoded viruses in vivo. For example, infection phenotypes, immunogenicity, and protective efficacy induced by CpG-recoded viruses in different age groups were not studied yet. This is important, because attenuation of infection phenotypes caused by recoded viruses may depend on the population-based expression of cellular components targeting viral CpG dinucleotides. In the present study, we generated several Zika virus (ZIKV) variants with the increasing CpG content and compared infection in neonatal and adult mice. Increasing the CpG content caused host-age-dependent attenuation of infection with considerable attenuation in neonates and high attenuation in adults. Expression of the zinc-finger antiviral protein (ZAP)—the host protein targeting viral CpG dinucleotides—was also age-dependent. Similar to the wild-type virus, ZIKV variants with the increased CpG content evoked robust cellular and humoral immune responses and protection against lethal challenge. Collectively, the host age should be accounted for in future studies on mechanisms targeting viral CpG dinucleotides, development of safe dinucleotide recoding strategies, and applications of CpG-recoded vaccines.
Highlights
Dinucleotide frequencies deviate from what is randomly expected [1]; the most striking example is the suppression of cytosine-phosphate-guanine (CpG) dinucleotide frequencies in vertebrates and most vertebrate RNA viruses [2, 3]
In silico analysis demonstrated that WT Zika virus (ZIKV) genomes, as expected, had suppression of CpG dinucleotides (Figure 2A)
In support of the host-age-dependent attenuation of infection phenotypes caused by CpG-recoded viruses we demonstrated that expression of zinc-finger antiviral protein (ZAP)—the host protein targeting viral CpG dinucleotides—is age-dependent
Summary
Dinucleotide frequencies deviate from what is randomly expected [1]; the most striking example is the suppression of cytosine-phosphate-guanine (CpG) dinucleotide frequencies in vertebrates and most vertebrate RNA viruses [2, 3]. Experimental increase of CpG dinucleotides in a relatively small region of an RNA viral genome, while retaining the amino acid composition of encoded proteins, impairs infection in vitro and in vivo [4,5,6,7,8,9] providing a promising approach for live modified vaccines. Cytosine-phosphate-guanine dinucleotide recoding is an emerging vaccine approach, so. Zinc-finger antiviral protein (ZAP) targets recoded human immunodeficiency virus 1 (HIV-1) and echovirus 7 by directly binding to CpG-enriched genomic regions [9, 14]; subsequently, synergy or complementation of ZAP function by oligoadenylate synthetase 3, RNase L [15] and cytoplasmic protein KHNYN [16] is capable of inhibiting replication of viruses containing the elevated number of CpG dinucleotides
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