Human Papillomavirus(HPV): an Overview

Sanjiv Rughooputh and Pamela Greenwell
Molecular and Medical Microbiology Research Group University of Westminster London W1 W6UW, UK.
Corresponding author : Dr Sanjiv Rughooputh.

HPV are a group of heterogeneous viruses that contain many genotypes. These viruses can be divided into high risk and low risk types, depending on their association with disease. There are about seventy types of HPV that can infect epithelial surfaces differentially. HPV have been implicated in the aetiology of cervical cancer, the most common form of malignant tumour in women worldwide.

Infections with HPV in the form of skin warts were recognized as long as 500 BC. However, there was no real interest in these viruses until they were linked with genital cancers . Transmission of HPV as judged by the presence of genital warts has for centuries been known to be associated with sexual intercourse. However, it was only in 1954 that Barret, Silber and McGinley confirmed the sexual transmission of HPV. They studied American servicemen returning from the Korean war, who developed penile warts after having intercourse with Korean women.

This heterogeneous group of viruses has the ability to infect and replicate in squamous epithelia of both keratinised and mucosal surfaces. Most of the viral types infect cutaneously, but a number are mucotropic infecting the oral cavity and the urogenital tract. HPV can multiply on virtually any part of the body surface and their DNA may then integrate into the human genomic DNA. Infection with HPV is quite common. Nonetheless not all infections lead to malignancy. Infections with HPV lead to a variety of problems including common warts and verruca to malignant disease such as cancer of cervix and larynx. HPV, is one of the two genera of papovaviridae, papilloma originates from the Latin word papilla meaning nipple, while oma means tumour producing.

HPV consists of a capsid that has icosahedral symmetry with 72 capsomeres of average diameter between 52-55nm. HPV contains double stranded DNA (dsDNA) molecules coding for the proteins of estimated weight of 5X106 Da and a genome size of 8Kb. The molecular organization of the HPV genome is well conserved between viruses of various types. The ORF (open reading frame) is divided into two areas coding for E (early) and L (late) proteins. Because of the overlapping nature of ORFs the mRNA transcribed is complex and it is not clear which transcript codes for which protein. The ORFs are situated on and are transcribed from the same strand and so are read in the same direction from 5 to 3.

The most studied are E6 and E7. These are important for the efficient immortalization of human keratinocytes. The early proteins E6 and E7 are both made in the basal or parabasal cells, while the E4 proteins are made suprabasally in differentiating cells. E4 is found early in infection, but can accumulate in the late phase.

E5 is a membrane associated hydrophilic protein that has cell transformation potential. This role is enhanced in the presence of epidermal growth factors. The other early proteins of interest are E1 and E2.

E2 has two roles in the life cycle of HPV and it has been suggested that the disruption of the E2 gene in high risk HPV16 is an important precursor in the process of cervical carcinogenesis. E2 can regulate transcription from the early promoter and contains a transactivating domain at the 5 end and a DNA binding domain at the 3 end. However the role of E2 during keratinocyte differentiation is poorly understood.

Late proteins L1 and L2 are the major and minor capsid proteins of the virion. L1 is found in the highly differentiated upper spinous layers. Since these proteins are made in the epithelial cells, it is difficult for the immune system to recognise them. Infections with HPV can start out as a simple papilloma, which given the right conditions can progress into a metastatic carcinoma. HPV penetrates skin by infecting the basal cell layer. Following entry into the host cell and uncoating, the viral genome migrates to the nucleus where transcription, DNA replication and virion assembly occur. The early genes are copied from a single promoter and the transcripts are subjected to differential splicing to generate mRNA for the seven early proteins. These include regulatory proteins, some with transactivating properties, which depress the genes for certain cellular enzymes and stimulate cellular DNA synthesis. The viral genome replicates only very slowly as an autonomous plasmid in the nuclei of these cells. However, in the terminally differentiated cells that comprise the outer layers of the epithelium, full expression of the viral genome and DNA synthesis occur. Late genes are transcribed from a second promoter. The late genes encode structural proteins L1 and L2, which after various posttranslational modifications are directed to the nucleus via their nuclear localization signals to be assembled into virions.

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