Virus adaptation to human host is an interesting aspect of virus evolution, especially in the context of emerging pathogens. CpG depletion is a well-known phenomenon in viruses during adaptation. Various reports have linked overrepresented CpG dinucleotides to restriction of viral replication in the host due to host factors like Zinc-finger antiviral protein (ZAP) for RNA viruses , TLR9 responses and deamination of methylated cytosines for DNA viruses.

 

Hepatitis C virus (HCV) is a bloodborne pathogen that can cause chronic liver disease and hepatocellular carcinoma. The loss of CpGs from virus genomes allows escape from restriction by the host zinc-finger antiviral protein (ZAP). The evolution of HCV in the human host has not been explored in the context of CpG depletion. We analysed 2616 full-length HCV genomes from 1977 to 2021. During the four decades of evolution in humans, we found that HCV genomes have become significantly depleted in (a) CpG numbers, (b) CpG O/E ratios (i.e relative abundance of CpGs), and (c) the number of ZAP-binding motifs.

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Interestingly, our data suggests that the loss of ZAP-binding motifs primarily drives the loss of CpGs in HCV genomes over time; thus suggesting a yet unknown role for ZAP-mediated selection pressures in HCV evolution. The HCV core gene is significantly enriched for the number of CpGs and ZAP-binding motifs. In contrast to the rest of the HCV genome, the loss of CpGs from the core gene does not appear to be driven by ZAP-mediated selection. This work highlights CpG depletion in HCV genomes during their evolution in humans and the role of ZAP-mediated selection in HCV evolution.