Abstract
ABSTRACT Human papillomaviruses (HPVs) replicate in the cutaneous and mucosal epithelia, and the infectious cycle is synchronous with the differentiation program of the host keratinocytes. The virus initially infects dividing cells in the lower layers of the epithelium, where it establishes a persistent infection. The viral genome is maintained as a low-copy-number, extrachromosomal element in these proliferating cells but switches to the late stage of the life cycle in differentiated cells. The cellular chromatin adaptor protein Brd4 is involved in several stages and processes of the viral life cycle. In concert with the viral transcriptional regulator E2, Brd4 can repress transcription from the early viral promoter. Brd4 and E2 form a complex with the viral genome that associates with host chromosomes to partition the viral genome in dividing cells; Brd4 also localizes to active sites of productive HPV DNA replication. However, because of the difficulties in producing HPV viral particles, the role of Brd4 in modulating viral transcription and replication at the initial stage of infection is unclear. In this study, we have used an HPV18 quasivirus-based genome delivery system to assess the role of Brd4 in the initial infectivity of primary human keratinocytes. We show that, upon infection of primary human keratinocytes with HPV18 quasivirus, Brd4 activates viral transcription and replication. Furthermore, this activation is independent of the functional interaction between Brd4 and the HPV18 E2 protein.
Highlights
Human papillomaviruses (HPVs) are an ancient group of nonenveloped, double-stranded, circular DNA viruses that exhibit exquisite species specificity and mucosal or cutaneous epithelial cell tropism
Previous studies have shown that HPV16 and HPV31 genomes can be packaged in recombinant HPV16 virus-like particles (VLPs), and the resulting quasiviruses can infect keratinocyte cell lines, such as HaCaT [11]
We have shown that HPV18 genomes can be packaged in HPV18 VLPs, and these HPV18 quasiviruses can infect primary keratinocytes [42]
Summary
Human papillomaviruses (HPVs) are an ancient group of nonenveloped, double-stranded, circular DNA viruses that exhibit exquisite species specificity and mucosal or cutaneous epithelial cell tropism. Initiation of a viral gene expression program produces the E1 and E2 replication proteins, which are required to replicate the incoming viral genome to low levels to establish infection [4] In the stage of infection, the viral genome replicates in synchrony with the host DNA and is partitioned to daughter cells. When these infected cells move upward through the epithelium and differentiate, late transcription is activated, leading to a massive upregulation of the E1 and E2 viral replication proteins, with a resulting amplification of viral genomes to a high copy number. Less is known about the transcriptional effect of E2 on replicating extrachromosomal genomes, and one study indicates that these genomes may be more impervious to the repressive function of E2 [28]
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