Transmission Sexually transmitted HPV is divided into two categories: low-risk and high-risk. Low-risk HPVs cause warts on or around the genitals. Types 6 and 11 cause 90% of all genital warts and recurrent respiratory papillomatosis, which causes benign tumors in the air passages. High-risk HPVs cause cancer and consist of about twelve identified types. Risk factors for persistent genital HPV infections, which increase the risk of developing cancer, include early age of first sexual intercourse, multiple partners, smoking, and immunosuppression. HPV is difficult to remove via standard hospital disinfection techniques and may be transmitted in a healthcare setting on re-usable gynecological equipment, such as vaginal ultrasound transducers. The communicability period remains unknown, but likely at least as long as visible HPV lesions persist. HPV may still be transmitted even after lesions are treated and no longer visible or present.
Perinatal Although genital HPV types can be transmitted from mother to child during birth, the appearance of genital HPV-related diseases in newborns is rare. However, the lack of appearance does not rule out asymptomatic latent infection, as the virus has proven capable of hiding for decades.
Perinatal transmission of HPV types 6 and 11 can result in the development of juvenile-onset recurrent
respiratory papillomatosis (JORRP). JORRP is very rare, with rates of about 2 cases per 100,000 children in the United States.
Genital infections Genital HPV infections are transmitted primarily by contact with the genitals, anus, or mouth of an infected sexual partner. Of the 120 known human papillomaviruses, 51 species and three subtypes infect the genital mucosa. Fifteen are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), three as probable high-risk (26, 53, and 66), and twelve as low-risk (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and 89).
Hands Studies have shown HPV transmission between the hands and genitals of the same person and sexual partners. Hernandez tested the genitals and dominant hand of each person in 25 heterosexual couples every other month for an average of seven months. She found two couples where the man's genitals infected the woman's hand with high-risk HPV, two where her hand infected his genitals, one where her genitals infected his hand, two each where he infected his own hand, and she infected her own hand. Hands were not the main source of transmission in these 25 couples, but they were significant. Partridge reports men's fingertips became positive for high-risk HPV at more than half the rate (26% per two years) as their genitals (48%). Winer reports 14% of fingertip samples from sexually active women were positive. Non-sexual hand contact seems to have little or no role in HPV transmission. Winer found all fourteen fingertip samples from virgin women negative at the start of her fingertip study.
Shared objects Sharing of possibly contaminated objects, for example, razors, Although possible, transmission by routes other than sexual intercourse is less common for female genital HPV infection.
Blood Though it has traditionally been assumed that HPV is not transmissible via blood, as it is thought to infect only cutaneous and mucosal tissues, recent studies have called this notion into question. Historically, HPV DNA has been detected in the blood of cervical cancer patients. In 2005, a group reported that, in frozen blood samples of 57 sexually naive pediatric patients who had
vertical or
transfusion-acquired HIV infection, 8 (14.0%) of these samples also tested positive for HPV-16. This seems to indicate that it may be possible for HPV to be transmitted via
blood transfusion. However, as non-sexual transmission of HPV by other means is not uncommon, this could not be definitively proven. In 2009, a group tested
Australian Red Cross blood samples from 180 healthy male donors for HPV, and subsequently found DNA of one or more virus strains in 15 (8.3%) of the samples. However, it is important to note that detecting the presence of HPV DNA in blood is not the same as detecting the virus itself in blood, and whether or not the virus itself can or does reside in blood in infected individuals is still unknown. As such, it remains to be determined whether HPV can or cannot be transmitted via blood.
Surgery Hospital transmission of HPV, especially to surgical staff, has been documented. Surgeons, including urologists and/or anyone in the room, are subject to HPV infection by inhalation of noxious viral particles during
electrocautery or
laser ablation of a condyloma (wart). There has been a case report of a laser surgeon who developed extensive laryngeal papillomatosis after providing laser ablation to patients with anogenital condylomata. HPV infection is limited to the
basal cells of
stratified epithelium, the only tissue in which they replicate. The virus cannot bind to live tissue; instead, it infects
epithelial tissues through micro-abrasions or other epithelial trauma that exposes segments of the
basement membrane. HPV is a small double-stranded circular DNA virus with a genome of approximately 8000 base pairs. The HPV life cycle strictly follows the differentiation program of the host keratinocyte. It is thought that the HPV
virion infects
epithelial tissues through micro-abrasions, whereby the virion associates with putative receptors such as alpha
integrins,
laminins, and
annexin A2 leading to the entry of the virions into
basal epithelial cells through
clathrin-
mediated endocytosis and/or
caveolin-mediated endocytosis depending on the type of HPV. At this point, the viral
genome is transported to the nucleus by unknown mechanisms and establishes itself at a copy number of 10-200 viral genomes per cell. A sophisticated
transcriptional cascade then occurs as the host keratinocyte begins to divide and become increasingly differentiated in the upper layers of the epithelium.
Evolution The phylogeny of HPV strains generally reflects the migration patterns of
Homo sapiens and suggests that HPV may have diversified along with the human population. Studies suggest that HPV evolved along five major branches that reflect the ethnicity of human hosts and diversified with the human population. Researchers initially identified two major variants of HPV16, European (HPV16-E), and Non-European (HPV16-NE). More recent analyses based on thousands of HPV16 genomes show that indeed two major clades exist, that are further subdivided into four lineages (designated A-D) and even further subdivided into 16 sublineages (A1–4, B1–4, C1–4 and D1–4). The A1-A3 sublineages constitute the European variant, A4 the Asian variant, B1-B4 the African type I variant, C1–C4 the African type II variant, D1 the North American variant, D2 the Asian American type I variant, D3 the Asian American type II variant. Although HPV16 is a DNA virus, there are signs of recombination among the different lineages. Based on an analysis of more than 3600 genomes, between 0.3 and 1.2% of them could be recombinant. The two primary oncoproteins of high-risk HPV types are E6 and E7. The "E" designation indicates that these two proteins are
early proteins (expressed early in the HPV life cycle). The "L" designation indicates that they are
late proteins (late expression). After the host cell is infected viral early promoter is activated. A polycistronic primary RNA containing all six early ORFs is transcribed. This polycistronic RNA then undergoes active RNA splicing to generate multiple isoforms of
mRNAs. One of the spliced isoform RNAs, E6*I, serves as an E7 mRNA to translate E7 protein. However, viral early transcription subjects to viral E2 regulation and high E2 levels repress the transcription. HPV genomes integrate into the host genome by disrupting the E2 ORF, preventing E2 repression of E6 and E7. Thus, viral genome integration into the host DNA genome increases E6 and E7 expression by promoting cellular proliferation and the chance of malignancy. The degree to which E6 and E7 are expressed is correlated with the type of cervical lesion that can ultimately develop. The E6/E7 proteins inactivate two tumor suppressor proteins,
p53 (inactivated by E6) and
pRb (inactivated by E7). The viral
oncogenes E6 and E7 are thought to modify the cell cycle so as to retain the differentiating host keratinocyte in a state that is favourable to the amplification of viral genome replication and consequent late gene expression. E6, in association with the host E6-associated protein, which has ubiquitin ligase activity, ubiquitinates p53, leading to its proteosomal degradation. E7 (in oncogenic HPVs) acts as the primary transforming protein. E7 competes for
retinoblastoma protein (pRb) binding, freeing the transcription factor
E2F to transactivate its targets; thus, pushing the cell cycle forward. All HPV strains can induce transient proliferation, but only strains 16 and 18 can immortalize cell lines
in vitro. It has also been shown that HPV 16 and 18 cannot immortalize primary
rat cells alone; there needs to be activation of the
ras oncogene. In the upper layers of the host epithelium, the late genes L1 and L2 are transcribed/translated and serve as structural proteins that encapsidate the amplified viral genomes. Once the genome is encapsidated, the capsid appears to undergo a redox-dependent assembly/maturation event, which is tied to a natural redox gradient spanning both suprabasal and cornified epithelial tissue layers. This assembly/maturation event stabilizes virions and increases their specific infectivity. Virions can then be sloughed off in the dead
squames of the host epithelium and the viral lifecycle continues. A 2010 study has found that E6 and E7 are involved in
beta-catenin nuclear accumulation and activation of
Wnt signaling in HPV-induced cancers.
Latency period Once an HPV virion invades a cell, an active infection occurs, and the virus can be transmitted. Several months to years may elapse before squamous intraepithelial lesions (SIL) develop and are clinically detected. The time from active infection to clinically detectable disease may make it difficult for epidemiologists to establish which partner was the source of infection.
Clearance Most people clear HPV infections without medical action or consequences. The table provides data on high-risk types (i.e., the types found in cancers). Clearing an infection does not always create immunity if there is a new or continuing source of infection. Hernandez's 2005-6 study of 25 couples reports "A number of instances indicated apparent reinfection [from partner] after viral clearance." ==Diagnosis==