CpG-Recoding in Zika Virus Genome Causes Host-Age-Dependent Attenuation of Infection With Protection Against Lethal Heterologous Challenge in Mice

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.

Zika Virus with Increased CpG Dinucleotide Frequencies Shows Oncolytic Activity in Glioblastoma Stem Cells

“…Efficacy of the CpG-recoded influenza virus vaccine has been demonstrated in mice; we also showed full protection evoked by CpG-recoded Zika virus (ZIKV) vaccine candidates in mice challenged with lethal heterologous ZIKV [7].…”

“…In silico recoding and recovery of CpG-modified ZIKV variants were previously described [7]. The MUTATE SEQUENCES program in the SSE 1.3 software package (Peter Simmonds, University of Oxford, Oxford, UK) [28] was used to modify the sequence of the contemporary Asian ZIKV H/PF/2013 strain [GenBank: KJ776791.2] [29] and to generate variants with increased CpG numbers in regions encoding envelope (E) and nonstructural 1 (NS1) proteins ( Figure 1).…”

Comparative Genomics and Integrated Network Approach Unveiled Undirected Phylogeny Patterns, Co-mutational Hotspots, Functional Crosstalk and Regulatory Interactions in SARS-CoV-2

“…Apart from this, CpG oligodeoxynucleotides (ODNs) are known to act as adjuvants and are already established as a potent stimulator for host immune system (Campbell, 2017; Becker, 2005; Yuan, 2017; Singh et al, 2016; Yu et al, 2018). Moreover, recent studies conducted on influenza A genome and Zika virus genome has shown that by increasing the CpG dinucleotides in viral genome, impairment of viral infection is observed (Gaunt et al, 2016; Trus et al, 2020). Our result showed that the presence of conserved CpG islands in Nps1 and N protein across 245 genomes of SARS-CoV-2 indicated their role in pathogenesis and can be targeted by Zinc Finger Antiviral Proteins or exploited to design CpG-recoded vaccines.…”

The Roles of Host 5-Methylcytosine RNA Methyltransferases during Viral Infections

“…It is known that experimental increase in the pools of CpG dinucleotides in CpG-deficient viral genomes may lead to significant decrease in viral replication and virulence [59][60][61]. Thus, it may suggest that m 5 C RNA methyltransferases may play an important role during the recognition of viral CpG and the inhibition of replication process of selected types of viruses.…”