Keratinocyte Differentiation-Dependent Human Papillomavirus Gene Regulation

Abstract

Human papillomaviruses (HPVs) cause diseases ranging from benign warts to invasive cancers. HPVs infect epithelial cells and their replication cycle is tightly linked with the differentiation process of the infected keratinocyte. The normal replication cycle involves an early and a late phase. The early phase encompasses viral entry and initial genome replication, stimulation of cell division and inhibition of apoptosis in the infected cell. Late events in the HPV life cycle include viral genome amplification, virion formation, and release into the environment from the surface of the epithelium. The main proteins required at the late stage of infection for viral genome amplification include E1, E2, E4 and E5. The late proteins L1 and L2 are structural proteins that form the viral capsid. Regulation of these late events involves both cellular and viral proteins. The late viral mRNAs are expressed from a specific late promoter but final late mRNA levels in the infected cell are controlled by splicing, polyadenylation, nuclear export and RNA stability. Viral late protein expression is also controlled at the level of translation. This review will discuss current knowledge of how HPV late gene expression is regulated.

Factors That Govern the Induction of Long-Lived Antibody Responses

“…(ii) Similarly, after HPV infects its target cells, basal epithelial cells, the virus remains intracellular and not accessible to antibodies. The HPV lifecycle is intimately tied to the differentiation of basal cells into terminally differentiated epithelial cells [2]. Only when these cells differentiate are HPV virions produced and released.…”

Proteomic and bioinformatic analysis of condyloma acuminata: mild hyperthermia treatment reveals compromised HPV infectivity of keratinocytes via regulation of metabolism, differentiation and anti-viral responses

“…metabolic enzymes or related signaling pathways to enhance energy production in keratinocytes [24], elevate protein synthesis [25] and promote cellular proliferation [26]. Besides, the complete differentiation and keratinization procedure of keratinocytes also plays an additional pivotal role in the life cycle of HPVs [27]. By coupling with normal epithelium developmental processes, HPVs can impede regular immune responses [28], and therefore escape identification and elimination by intrinsic and innate immunities.…”

Differential expression of human papillomavirus 16-, 18-, 52-, and 58-derived transcripts in cervical intraepithelial neoplasia

“…Subsequently, expression of the E1^E4 splicing site was evaluated. Positivity of this site is related to both early and late gene expression [19]. First, we compared E1^E4 expression levels across CIN grades and found its highest expression in CIN3 ( Fig 3A).…”

“…To represent the viral life cycle, we focused on the expression levels of HPV-derived transcripts E6/E6*, E1^E4, and L1. E6/E6* are oncogenes regulated by the early promoter, the E1^E4 splicing site relates to both early and late gene expression and can contribute to viral replication, and L1 expression is observed in the late phase of viral differentiation, which is regulated by the late promoter [19]. In addition to HPV 16 and 18, we focused on HPV 52 and 58, which are highly prevalent in East Asia [20].…”