Papillomaviruses may be classified into distinct groups based on the host that they infect.
Structure:
Papillomaviruses are small (50-60 nm), nonenveloped, icosahedral DNA viruses that encode for up to 80 early and 2 late genes. The open reading frames (ORFs) of the virus genomes are designated E1 to E7 and L1 and L2, where “E” denotes early and “L” denotes late. L1 and L2 code for virus capsid proteins. The early genes are associated with functions cuh as viral replication and cellular transformation. Cook (US 6,602,697)
Human papillomaviruses (HPV)
Human papillomavirus (HPV) causes ~4.5% of all human cancers, including tumours of the cervix, anus, vagina, penis, oropharynx, vulva, oral cavity, and larynx. Cervical cancer is the most common of these, with 604,000 new cases and 342,000 deaths per year, virtually all attributable to HPV. However, the majority of HPV types (genotypes) do not cause cancer; of 448 types that have been documented, only 12 are currently classified as carcinogenic: types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. Infections by these carcinogenic HPV types are extremely common, but ~80% are cleared by the immune system within three years, and only ~3% progress to cervical precancer/cancer within 7 years. HPV16 and HPV18 are the most common carcinogenic types, together responsible for ~71% of cervical cancers.
Structure: HPV belongs to the papovavirus family have naked icosahedral symmetry and a double stranded small circular DNA genome. HPVs are a family of small DNA viruses with a pronounced tropism for epithelial cells. HPV are further classified into more than 70 types based on DNA sequence homology. Papillomavirus types appear to be type specific immunogens in that a neutralizing immunity to infection to one type of papillomavirus does not confer immunity against another type of papillomavirus. Cook (US 6,602,697)
HPVs have circular, ~7.9 kb double-stranded DNA genomes consisting of an upstream regulatory region (URR), an intergenic noncoding region (NCR) with simple (AT)n and poly-T repeats, and eight main expressed protein-coding open reading frames (ORFs). The ORFs are named according to their approximate timing of expression during the viral life cycle, where ‘E’ denotes early and ‘L’ denotes late: E6, E7, E1, E2, E4, E5, L2, and L1. E6 and E7 are the primary HPV oncoproteins. In carcinogenic types, E6 and E7 degrade p53 and pRb, respectively.
Transmission/Cell Entry: HPV is transmitted through close direct, often sexual contact and replicates in the epithelium/mucosa. Infection of cells induces cell proliferation and warts. Diagnosis is via papanicolaou (PAP) smears (hybridization with strain specific DNA probes).
Human Papillomavirus (HPV) replicates as a small, extrachromosomal circle of DNA (episome), completely separate from the host cell’s chromosomes, during most of its lifecycle. However, in some cases, the viral genome can accidentally integrate into the host’s chromosome, which is a key event in the development of HPV-related cancers.
During infectious entry into host keratinocytes, HPV particles interact with many host proteins, beginning with major capsid protein L1 binding to cellular heparan sulfate and a series of enzymatic capsid modifications that promote infectious cellular entry. After utilizing the endosomal pathway to uncoat the viral genome (vDNA), the minor capsid protein L2/vDNA complex is retrograde trafficked to the Golgi, and thereafter, to the nucleus where viral transcription initiates. Post-Golgi trafficking is dependent on mitosis, with L2-dependent tethering of vDNA to mitotic chromosomes prior to accumulation at nuclear substructures in G1. See Campos
Disease mechanism/pathology: Infection with HPV usually causes papillomatous hyperplasia (warts) but lesions cause by a subset of these viruses (e.g., HPV-16, -18, -31, or -33) have a propensity for malignat progression. Warts which are caused by HPV can be surgically removed or spontaneously regress. Laryngeal papillomas require surgery. Currently in Phase II clinical trials are recombinant papillomavirus structural (capsid) protein vaccines which successfully prevent cervical cancer.
During malignant progression, the HPV genome frequently integrates into the host DNA resulting in the expression of only two viral proteins, E6 and E7. E6 and E7 are viral proteins that interfere with the normal regulation of the cell cycle and apoptosis. During a normal cell cycle, the retinoblastoma protein (pRb) controls the activity of a transcription factor called E2F. When pRb is bound to E2F, progress through the cell cycle is prevented. When cellular conditions are right for cell growth and division, pRb releases E2F, which then promotes cell cycle progression.
The viral E7 protein binds to Rb, releasing E2F regardless of whether cell division should occur. This forces cell division when an infected cell is receiving signals to not divide. Fortunately, a mechanism exists to prevent this aberrant cell division. If levels of E2F become abnromally high as they do when E7 forces release of E2F from Rb, a host cell protein called p53 triggers apoptosis. However, the virus can overcome this mechanisms when the viral E6 protein binds and inactivates p53.
The host tissue of human papillomaviruses is the stratified epithelium. This tissue is complex in that it is composed of layered sheets of nondividing cells in various stages of terminal differentiation, with the uppermost layer being the most differentiated. Only cells of the bottom-most layer of this tissue, the basal cells, proliferate. Although the HPV life cycle begins with the infection of a basal cell, it only comes to completion when the infected cell reaches the upper layers of the epithelium. As a consequence, the HPV DNA initially finds itself in the nucleus of a proliferating cell, but later in that of a differentiating (nonproliferating) one. This sequential mixture of cell states that the virus has to contend with has undoubtedly shaped the way by which HPV replicates its DNA throughout the varying milieux during its life cycle.
Detection: HPV can be detected by PAP smear which takes only minutes to do. It is recommended that all women, especially those between 35 and 64 be tested. If negative, it is recommended to do another PAP every 3 years.
Prevention & Treatment: There is currently no known treatment which exists that can cure the virus. However, there are 2 vaccines:
1) Cervarix: prevents infection against the the 2 types of HPV which cuase the majority of cases of utirine cancer.
2) Gardasil (Huamn Papillomavirus Quadrivalent –Types 6, 11, 16 and 18 –Merck) vaccine: prevents infection against the 16 and 18 types of virus and also the 6 and 11 types which cause genital warts.