Evolution of cocirculating Varicella-Zoster Virus genotypes during a Chickenpox outbreak in Guinea-Bissau

Varicella-zoster virus (VZV), a double-stranded DNA alphaherpesvirus, is associated with seasonal outbreaks of varicella in
nonimmunized populations. Little is known about whether these outbreaks are associated with a single or multiple viral genotypes and whether new mutations rapidly accumulate during transmission. Here, we take advantage of a well-characterized population cohort in Guinea-Bissau and produce a unique set of 23 full-length genome sequences, collected over 7 months from eight households. Comparative sequence analysis reveals that four distinct genotypes cocirculated among the population, three of which were present during the first week of the outbreak, although no patients were coinfected, which indicates that exposure to infectious virus from multiple sources is common during VZV outbreaks. Transmission of VZV was associated with length
polymorphisms in the R1 repeat region and the origin of DNA replication. In two cases, these were associated with the formation
of distinct lineages and point to the possible coevolution of these loci, despite the lack of any known functional link in VZV or
related herpesviruses. We show that these and all other sequenced clade 5 viruses possess a distinct R1 repeat motif that increases the acidity of an ORF11p protein domain and postulate that this has either arisen or been lost following divergence of the major
clades. Thus, sequencing of whole VZV genomes collected during an outbreak has provided novel insights into VZV biology,
transmission patterns, and (recent) natural history.