Persistent Human Papillomavirus Infection

Abstract

Persistent infection with oncogenic human papillomavirus (HPV) types is responsible for ~5% of human cancers. The HPV infectious cycle can sustain long-term infection in stratified epithelia because viral DNA is maintained as low copy number extrachromosomal plasmids in the dividing basal cells of a lesion, while progeny viral genomes are amplified to large numbers in differentiated superficial cells. The viral E1 and E2 proteins initiate viral DNA replication and maintain and partition viral genomes, in concert with the cellular replication machinery. Additionally, the E5, E6, and E7 proteins are required to evade host immune responses and to produce a cellular environment that supports viral DNA replication. An unfortunate consequence of the manipulation of cellular proliferation and differentiation is that cells become at high risk for carcinogenesis.

Dangerous Liaisons: Long-Term Replication with an Extrachromosomal HPV Genome

“…Many HPVs also contain genes for smaller, less well conserved proteins such as E5, E6, and E7. These accessory proteins are essential for immune evasion and for manipulating the cellular environment to support the viral lifecycle in a stratified host epithelium [ 4 ].…”

“…The E5, E6, and E7 proteins support the differentiation-dependent life cycle of HPVs by manipulating the balance of cellular proliferation and differentiation, and by antagonizing innate immune pathways [ 4 ]. Although all HPVs have similar strategies, the precise way in which certain HPVs exploit host pathways is different and can promote genetic instability and oncogenesis [ 76 , 77 , 78 , 79 ].…”

Multiple Roles of Brd4 in the Infectious Cycle of Human Papillomaviruses

“…There are four viral proteins that are conserved in all papillomaviruses: the L1 and L2 capsid proteins and the E1 and E2 replication proteins. The other proteins E5, E6, E7, and E4 can be considered accessory proteins that shape the cellular environment to support each stage of the viral infection (Della Fera et al, 2021). They do this by changing the balance of cellular proliferation and differentiation and by interfering with immune detection of the virus (Della Fera et al, 2021).…”

“…The other proteins E5, E6, E7, and E4 can be considered accessory proteins that shape the cellular environment to support each stage of the viral infection (Della Fera et al, 2021). They do this by changing the balance of cellular proliferation and differentiation and by interfering with immune detection of the virus (Della Fera et al, 2021). In this review, we will focus on the E1 and E2 replication/ transcription regulatory proteins that are involved in viral processes that intersect with the Brd4 protein.…”

“…This necessitates locating in euchromatic regions of the nucleus to avoid transcriptional silencing (Bestor, 2000). The viral genomes must also become "established" in the host cell nucleus: this requires evading cellular sensors that detect foreign DNA (Della Fera et al, 2021).…”