Virology of Human Papillomavirus Infections and The Link To Cancer - UpToDate

20/1/2020 Virology of human papillomavirus infections and the link to cancer - UpToDate
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Virology of human papillomavirus

infections and the link to cancer
Authors: Joel M Palefsky, MD, Ross D Cranston, MD
Section Editors: Don S Dizon, MD, FACP, David M Aboulafia, MD
Deputy Editor: Allyson Bloom, MD
All topics are updated as new evidence becomes available and our peer
review process is complete.
Literature review current through: Dec 2019. | This topic last

updated: Nov 21, 2019.
INTRODUCTION
Human papillomavirus (HPV) is the most common sexually

transmitted agent in the United States. The biology of these
viruses has been studied extensively and its link with
malignancies is well established, specifically with cancers
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involving the anogenital (cervical, vaginal, vulvar, penile,

anal) tract and those involving the head and neck. The
virology of HPV and its association with malignancy will be
reviewed here. The clinical manifestations, diagnosis,
epidemiology, prevention, and treatment of HPV infection
are discussed separately. (See "Human papillomavirus
infections: Epidemiology and disease associations".)
VIROLOGY
Human papillomavirus (HPV) is a small deoxyribonucleic

acid (DNA) virus of approximately 7900 base pairs. DNA
sequencing techniques have facilitated HPV typing and
characterization, with each type formally defined as distinct
by having less than 90 percent DNA base-pair homology
with any another HPV type [1]. There are over 40 HPV
types that infect the anogenital area.
HPV GENOTYPES AND RISK OF CANCER
HPV genotypes’ association with cancer risk varies, and is

reviewed below.
Cervical cancer — There is a broad separation of HPV

types based on their associated risk of cervical cancer:
● High-risk – This includes HPV 16, 18, 31, 33, 35, 39,
45, 51, 52, 56, 58, 59, and 68
● Low-risk – 6, 11, 40, 42, 43, 44, 53, 54, 61, 72, 73, and
81
Types 16 and 18 are the most commonly isolated HPV

types in cervical cancer, with type 16 found in
approximately 50 percent of patients [2]. However, not all
infections with HPV type 16 or 18 progress to cancer.
Furthermore, within single oncogenic HPV types, variants
exist that are associated with different oncogenic potential
[3]. The epidemiology of these high-risk types is discussed
separately. (See "Human papillomavirus infections:
Epidemiology and disease associations", section on
'Cervical cancer'.)
Head and neck cancer — HPV infection is associated with

some forms of oral squamous cell cancers, particularly
those of the oropharynx. There is an approximately two to
fourfold increased risk for cancers of the oral cavity and
oropharynx in patients infected with high-risk (oncogenic)
HPV types [4,5]. (See "Human papillomavirus-associated

head and neck cancer".)
Furthermore, the same sexual behaviors associated with

risk for anogenital HPV-related cancers may increase the
risk of HPV-related oropharyngeal squamous cell cancers,
particularly in those patients with HIV coinfection [6]. This
was shown in one study of men and women with and
without HIV, which reported that oral HPV infection was
common (34 percent). In individuals without HIV, risk for
HPV infection increased with number of recent orogenital or
oroanal sex partners. In individuals with HIV, risk increased
with lower CD4 T cell counts and increased number of
lifetime sex partners [7].
Anal cancer — HPV is also implicated in cancer of the

anus [1,8], and the spectrum of HPV types in the anal canal
is similar to that described in the cervix [8].
HPV 16 is the most commonly detected HPV type

associated with anal cancer [9-11]. However, the range of
HPV genotypes associated with anal cancer seems to
depend on whether or not it is occurring in the context of
HIV coinfection. As examples:
● One study evaluated HPV genotypes in anal swab

samples of men who have sex with men (MSM), with or
without associated HIV infection and isolated 29 and
10 HPV genotypes, respectively [8]. Despite this, the
range of HPV types was similar in both men with and
without HIV infection.
A few of the more commonly isolated HPV types in the

anal samples have only rarely been reported in cervical
samples (types 53, 58, 61, 70). HPV 32,
characteristically an oral HPV type, was also isolated
from anal samples and may indicate transmission by
oral-anal intercourse [8].
● In a cohort of 346 men with HIV and 262 men without

HIV, multiple anal HPV types were more common in
the participants with HIV (73 versus 23 percent). The
presence of multiple high-risk HPV types was
associated with significant immunosuppression (CD4 T
cell count below 200/mm3) in individuals with HIV.
This finding could reflect increased reporting of

receptive anal intercourse in this population or
increased HPV replication in patients with the acquired
immunodeficiency syndrome (AIDS) that is probably
related to failure of local mucosal immunity and

reactivation of HPV to reach detectable levels [8].
Penile cancer — HPV infection is also a risk factor for

carcinoma of the penis and intraepithelial neoplasia [12-14].
(See "Carcinoma of the penis: Epidemiology, risk factors,
and pathology".)
MOLECULAR PATHOGENESIS
The role of HPV infections in the etiology of epithelial

cancers has been supported by the following observations
[15]:
● HPV DNA is commonly present in anogenital

precancer and invasive cancers, as well as
oropharyngeal cancers
● Expression of the viral oncogenes E6 and E7 is

consistently demonstrated in lesional tissue
● The E6 and E7 gene products have transforming

properties by their interaction with growth-regulating
host cell proteins
● In cervical carcinoma cell lines, continued E6 and E7

expression is necessary to maintain the malignant
phenotype
● Epidemiologic studies indicate HPV infections as the

major factor for the development of cervical cancer
HPV proteins — The HPV genome encodes DNA

sequences for six early (E) proteins that are primarily
associated with viral gene regulation and cell
transformation, two late (L) proteins that form the shell of
the virus, and a region of regulatory DNA sequences known
as the long control region or upstream regulatory region
[16,17].
The two most important HPV proteins in the pathogenesis

of malignant disease are E6 and E7. Both E6 and E7
proteins are consistently expressed in HPV-carrying
anogenital malignant tumors, and they act in a cooperative
manner to immortalize epithelial cells [18]. At the molecular
level, the ability of E6 and E7 proteins to transform cells
relates in part to their interaction with two intracellular
proteins, p53 and retinoblastoma (Rb), respectively. (See
"Anal squamous intraepithelial lesions: Diagnosis,
screening, prevention, and treatment" and "Vaginal
intraepithelial neoplasia" and "Preinvasive and invasive

cervical neoplasia in HIV-infected women".)
Role of p53 protein — In the normal cell, the p53 protein is

a negative regulator of cell growth, controlling cell cycle
transit from G0/G1 to S phase, and also functions as a
tumor suppressor protein by halting cell growth after
chromosomal damage and allowing DNA repair enzymes to
function [19-22]. Following E6 binding of p53, p53 is
degraded in the presence of E6-associated protein [23].
This allows unchecked cellular cycling, and has an anti-
apoptotic effect, permitting the accumulation of
chromosomal mutations without DNA repair [24,25]. This
leads to chromosomal instability in high-risk HPV-containing
cells. The interaction of E6 with p53 may also affect
regulation and/or degradation of the Src family of
nonreceptor tyrosine kinases, potentially playing a role in
the stimulation of mitotic activity in infected cells [15,26].
In contrast to the E6 protein, E7 protein sensitizes wild-type

p53-containing cells to apoptosis, but exerts an anti-
apoptotic effect in cells with mutated p53 [27,28]. The
possible significance of this finding is discussed in the next
section. (See 'Progression from immortalization to
malignancy' below.)
Role of retinoblastoma protein — The Rb protein inhibits

the effect of positive growth regulation and halts cell growth
or induces cell apoptosis in response to DNA damage
[22,29]. One of the functions of Rb is to bind and render
inactive the E2F transcription factor. E2F controls DNA
synthesis and cyclin function and promotes the S phase of
cell cycling. E7 interacts with Rb protein via an E2F/Rb
protein complex. When E7 binds to Rb protein, E2F is
released and allows cyclin A to promote cell cycling [30,31].
The interaction of E7 with Rb may permit cells with
damaged DNA to bypass the G1 growth arrest normally
induced by wild-type p53 [32]. These processes allow
unchecked cell growth in the presence of genomic
instability that may lead to malignant change.
In support of the importance of E7 in cellular transformation,

inhibition of E7 binding to Rb abolishes its transforming
ability [33]. However, other mechanisms of E7-mediated cell
transformation probably also play a role. As an example,
several interactions of E7 with transcription factors have
been described [34,35], and E7 protein inactivates the
cyclin-dependent kinase inhibitors p21(CIP-1) and p27(KIP-
1), which may lead to growth stimulation of HPV-infected
cells [36,37].
Other proteins — Other HPV proteins that may be

involved in malignant transformation of a cell are E1
(regulation of DNA replication and maintaining the virus in
episomal form), E2 (cooperation with E1, viral DNA
replication, down-regulation of E6 and E7 expression), and
E5 (regulation of cell growth) [16]. The HPV genome exists
in two forms. Most commonly, it is found in a circular
episomal form that replicates autonomously outside the
host cell chromosome but within the host cell nucleus.
Under certain conditions associated with the development
and presence of high-grade squamous intraepithelial
lesions (HSIL) and cancer, the episome linearizes and
becomes integrated into the host cell genome. The site of
linearization in the episomal form is usually within the E2
viral gene and leads to an alteration of the E2 gene product,
disrupting the repressor functions of E2 and leading to
increased expression of the E6 and E7 oncoproteins [30]. In
one study, E2 produced growth arrest in HeLa cells by
repression of the E6 and E7 promoter; expression of E6
and E7 off a different promoter reversed the growth arrest
[38].
HIV infection — In addition to the effects of

immunosuppression, which promotes the persistence of
HPV infection, coinfection with HIV [39] may directly
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promote HPV-associated oncogenesis at the molecular

level. As an example, in vitro studies suggest that the HIV-
encoded tat protein may enhance expression of the HPV
E6 and E7 proteins [40]. In addition, HIV infection may
disrupt the mucosal epithelial barrier, potentiating the ability
of HPV virions to enter the epithelium and establish
infection through entry into basal epithelial cells [41]. (See
"Preinvasive and invasive cervical neoplasia in HIV-infected
women" and "HIV and women", section on 'Abnormal
cervical cytology'.)
Progression from immortalization to malignancy — In

vitro immortalization of human cells can be achieved in the
laboratory with either HPV E6 or E7, but cooperative
interaction between E6 and E7 enhances immortalization
efficiency. However, neither the individual genes nor their
cooperative interaction is sufficient to convert normal cells
to the malignant phenotype. There are two hypotheses for
how progression from immortalization to the malignant
phenotype occurs:
● There is some evidence that a separate signaling

cascade within or between cells blocks the progression
of immortalized cells to the malignant phenotype [42].
Oncogene transcription or viral oncoprotein expression
may be regulated in this manner via the retinoic acid

receptor [43], or by cytokines such as transforming
growth factor beta [44,45], interferon-alpha [46], or
tumor necrosis factor-alpha [47].
● Alterations in host cell DNA (eg, p53 mutations) may

interact with viral oncoproteins by acting in concert with
the oncogenes to permit progression from
immortalization to transformation [48]. Alternatively,
genetically unmodified, high-risk HPV-infected human
cells may be blocked from immortalization by
intracellular control of viral oncoprotein function [49].
These data suggest that intercellular cytokine-mediated

control plays an important role in suppression of malignant
transformation. Progression to the malignant phenotype
probably involves a genetic change in the pathways
controlling intracellular or intercellular signaling [15]. The
chromosomal instability that characterizes HPV infection
may be one mechanism leading to these genetic
modifications.
RISK FACTORS FOR HPV INFECTION
Genital HPV infections are considered to be spread by

unprotected penetrative intercourse or close skin-to-skin
physical contact involving an infected area [50]. Fomite,
digital/anal, and digital/vaginal contact probably may also
potentially spread the virus, although the evidence for this is
not definitive [50]. (See "Human papillomavirus infections:
Epidemiology and disease associations".)
Both primary (eg, the WHIM syndrome, described as Warts,

Hypogammaglobulinemia, Infections, and Myelokathexis [a
rare congenital disorder of the white blood cells that results
in chronic leukopenia and neutropenia]) and more
commonly, secondary immunodeficiency disorders (eg, HIV
infection) may predispose patients to HPV infections and to
the development of malignancies in affected tissues.
Although primary immunodeficiencies are rare, the
possibility of an underlying immune disorder should be
considered in patients with particularly severe or refractory
HPV infections. (See "Malignancy in primary
immunodeficiency", section on 'Human papillomavirus'.)
DETECTING HPV
The detection of HPV is facilitated by recent advances in

molecular biology. HPV testing is increasingly being used in
clinical management of patients. HPV testing falls into three

main categories [51]:
● HPV DNA testing – HPV DNA testing was the first

approach developed for routine clinical testing. Many
studies showed that the addition of HPV DNA testing to
cervical cytology improved the sensitivity for detection
of cervical cancer precursors, such as cervical
intraepithelial neoplasia (CIN) 2 and 3. However, the
specificity also decreased, resulting in the potential
unnecessary referral of women for colposcopy.
● HPV ribonucleic acid (RNA) testing – HPV RNA

testing, looking for expression of E6 and/or E7 RNA,
may be performed with the expectation that active HPV
oncogene expression would provide equivalent
sensitivity and better specificity than HPV DNA testing.
RNA-based testing has received US Food and Drug
Administration (FDA) approval for cervical HPV testing,
as it significantly improves the specificity of detecting
cervical intraepithelial neoplasia grade 2 and above
(CIN2+), thereby decreasing the number of "false-
positive" HPV tests compared with HPV DNA testing.
● Detection of cellular markers – Cellular marker

detection uses a different approach to diagnosing HPV-
associated disease. The HPV E7 protein disrupts cell

cycling, leading to an increase in cellular p16 protein
expression. High-grade CIN lesions contain high levels
of p16, and pathologists often immunostain cervical
biopsies to help distinguish between high-grade CIN
and immature squamous metaplasia, which is not
associated with HPV and is not precancerous. A large
study investigating the combination p16/Ki-67 dual-
stained cytology has demonstrated superior sensitivity
and noninferior specificity over Pap cytology to detect
cervical high-grade squamous intraepithelial lesions
(HSIL) dysplasia [52]. A p16-based test is FDA-
approved for screening at this time.
There are several HPV DNA tests that are currently

approved by the FDA for clinical use. These include Hybrid
Capture 2 (HC2), Cervista, and the PCR-based Cobas
4800 test. HC2 detects a cocktail of 13 different high-risk
(oncogenic) HPV types and reports the results as positive
for one or more of these types, or negative for all. The
Cervista and Cobas tests detect HPV 66 in addition to the
13 HPV types detected by HC2. The Cobas test identifies
HPV types 16 and 18, while detecting the remaining 12
types in a probe mix. The Cervista test indicates positivity
for one or more types in the 14-probe mix, but also offers
the option of testing for HPV 16/18 specifically. The Aptima

HPV test is an FDA-approved RNA-based test.
Indications for testing — The role of HPV testing is in

evolution:
● Cervical cancer screening – HPV testing as part of a

screening program for cervical cancer in women is
indicated either as a single, primary screening test
among women aged 25 years or older, or as cotesting
with a Pap test. The Cobas 4800 test is currently the
only test that is FDA-approved for primary HPV testing.
(See "Screening for cervical cancer" and "Invasive
cervical cancer: Epidemiology, risk factors, clinical
manifestations, and diagnosis".)
● Head and neck cancer – There is no role for HPV

testing of oral rinse or salivary specimens as a
screening test for oropharyngeal cancer. (See "Human
papillomavirus-associated head and neck cancer",
section on 'Clinicopathologic features'.)
● Anal cancer – The role for HPV testing in anal swab or

brush testing in screening for anal cancer, or anal high-
grade squamous intraepithelial lesions, the precursor
to anal cancer, is not clear. There are no
recommendations for anal HPV testing of populations

at high risk of anal cancer. These data are discussed
separately. (See "Anal squamous intraepithelial
lesions: Diagnosis, screening, prevention, and
treatment", section on 'Screening for anal SIL'.)
● Penile cancer – There are no clinically available tests

to screen for penile HPV infection for detection of
penile cancer or precancerous lesions. In addition,
HPV testing for men with penile cancer has no impact
on decision-making regarding treatment and is not
routinely performed. (See "Carcinoma of the penis:
Clinical presentation, diagnosis, and staging".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from

selected countries and regions around the world are
provided separately. (See "Society guideline links:
Treatment of cervical cancer".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials,

"The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to
6th grade reading level, and they answer the four or five key
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These articles are best for patients who want a general
overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer,
more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best
for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to

this topic. We encourage you to print or e-mail these topics
to your patients. (You can also locate patient education
articles on a variety of subjects by searching on "patient
info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Human

papillomavirus (HPV) (The Basics)")
● Beyond the Basics topics (see "Patient education:

Human papillomavirus (HPV) vaccine (Beyond the
Basics)" and "Patient education: Genital warts in
women (Beyond the Basics)" and "Patient education:

Cervical cancer screening (Beyond the Basics)")
SUMMARY
● Human papillomaviruses (HPVs) are small DNA

viruses that are sexually transmitted and associated
with squamous neoplasia of the anogenital region and
oropharynx. (See 'Virology' above and 'Introduction'
above.)
● There are multiple HPV genotypes that have differing

risks for causing malignancy; HPV types 16 and 18 are
highly prevalent in multiple types of cancer, including
cancers of the cervix, oropharynx, anus, and penis.
(See 'HPV Genotypes and risk of cancer' above.)
● The E6 and E7 genes of HPV 16 and 18 have a

particularly important role in the development of
malignancy through the interactions of their respective
protein products with the p53 tumor suppressor and
retinoblastoma (Rb). (See 'Molecular pathogenesis'
above.)
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REFERENCES
1. Tilston P. Anal human papillomavirus and anal cancer.

J Clin Pathol 1997; 50:625.
2. de Sanjose S, Quint WG, Alemany L, et al. Human

papillomavirus genotype attribution in invasive
cervical cancer: a retrospective cross-sectional
worldwide study. Lancet Oncol 2010; 11:1048.
3. Hildesheim A, Schiffman M, Bromley C, et al. Human

papillomavirus type 16 variants and risk of cervical
cancer. J Natl Cancer Inst 2001; 93:315.
4. Gillison ML, Koch WM, Capone RB, et al. Evidence

for a causal association between human
papillomavirus and a subset of head and neck
cancers. J Natl Cancer Inst 2000; 92:709.
5. Beachler DC, DʼSouza G. Oral human papillomavirus

infection and head and neck cancers in HIV-infected
individuals. Curr Opin Oncol 2013; 25:503.
6. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control

study of human papillomavirus and oropharyngeal
cancer. N Engl J Med 2007; 356:1944.
7. Beachler DC, Weber KM, Margolick JB, et al. Risk

factors for oral HPV infection among a high
prevalence population of HIV-positive and at-risk HIV-
negative adults. Cancer Epidemiol Biomarkers Prev
2012; 21:122.
8. Palefsky JM, Holly EA, Ralston ML, Jay N. Prevalence

and risk factors for human papillomavirus infection of
the anal canal in human immunodeficiency virus
(HIV)-positive and HIV-negative homosexual men. J
Infect Dis 1998; 177:361.
9. Bosch FX, Manos MM, Muñoz N, et al. Prevalence of

human papillomavirus in cervical cancer: a worldwide
perspective. International biological study on cervical
cancer (IBSCC) Study Group. J Natl Cancer Inst
1995; 87:796.
10. Zaki SR, Judd R, Coffield LM, et al. Human

papillomavirus infection and anal carcinoma.
Retrospective analysis by in situ hybridization and the
polymerase chain reaction. Am J Pathol 1992;

140:1345.
11. Frisch M, Glimelius B, van den Brule AJ, et al.

Sexually transmitted infection as a cause of anal
cancer. N Engl J Med 1997; 337:1350.
12. Maden C, Sherman KJ, Beckmann AM, et al. History

of circumcision, medical conditions, and sexual
activity and risk of penile cancer. J Natl Cancer Inst
1993; 85:19.
13. Varma VA, Sanchez-Lanier M, Unger ER, et al.

Association of human papillomavirus with penile
carcinoma: a study using polymerase chain reaction
and in situ hybridization. Hum Pathol 1991; 22:908.
14. Olesen TB, Sand FL, Rasmussen CL, et al.

Prevalence of human papillomavirus DNA and
p16INK4a in penile cancer and penile intraepithelial
neoplasia: a systematic review and meta-analysis.
Lancet Oncol 2019; 20:145.
15. zur Hausen H. Papillomaviruses causing cancer:

evasion from host-cell control in early events in
carcinogenesis. J Natl Cancer Inst 2000; 92:690.
16. Palefsky JM, Holly EA. Molecular virology and

epidemiology of human papillomavirus and cervical
cancer. Cancer Epidemiol Biomarkers Prev 1995;
4:415.
17. Palefsky JM. Anal human papillomavirus infection and

anal cancer in HIV-positive individuals: an emerging
problem. AIDS 1994; 8:283.
18. Münger K, Phelps WC, Bubb V, et al. The E6 and E7

genes of the human papillomavirus type 16 together
are necessary and sufficient for transformation of
primary human keratinocytes. J Virol 1989; 63:4417.
19. Vogelstein B, Fearon ER, Kern SE, et al. Allelotype of

colorectal carcinomas. Science 1989; 244:207.
20. Masuda H, Miller C, Koeffler HP, et al. Rearrangement

of the p53 gene in human osteogenic sarcomas. Proc
Natl Acad Sci U S A 1987; 84:7716.
21. Hinds P, Finlay C, Levine AJ. Mutation is required to

activate the p53 gene for cooperation with the ras
oncogene and transformation. J Virol 1989; 63:739.
22. Dupuy C, Buzoni-Gatel D, Touze A, et al. Cell

mediated immunity induced in mice by HPV 16 L1
virus-like particles. Microb Pathog 1997; 22:219.
23. Scheffner M, Huibregtse JM, Vierstra RD, Howley PM.

The HPV-16 E6 and E6-AP complex functions as a
ubiquitin-protein ligase in the ubiquitination of p53.
Cell 1993; 75:495.
24. Havre PA, Yuan J, Hedrick L, et al. p53 inactivation by

HPV16 E6 results in increased mutagenesis in human
cells. Cancer Res 1995; 55:4420.
25. Werness BA, Levine AJ, Howley PM. Association of

human papillomavirus types 16 and 18 E6 proteins
with p53. Science 1990; 248:76.
26. Oda H, Kumar S, Howley PM. Regulation of the Src

family tyrosine kinase Blk through E6AP-mediated
ubiquitination. Proc Natl Acad Sci U S A 1999;
96:9557.
27. Puthenveettil JA, Frederickson SM, Reznikoff CA.

Apoptosis in human papillomavirus16 E7-, but not E6-
immortalized human uroepithelial cells. Oncogene
1996; 13:1123.
28. Magal SS, Jackman A, Pei XF, et al. Induction of

apoptosis in human keratinocytes containing mutated
p53 alleles and its inhibition by both the E6 and E7

oncoproteins. Int J Cancer 1998; 75:96.
29. Pagano M, Dürst M, Joswig S, et al. Binding of the

human E2F transcription factor to the retinoblastoma
protein but not to cyclin A is abolished in HPV-16-
immortalized cells. Oncogene 1992; 7:1681.
30. Schwarz E, Freese UK, Gissmann L, et al. Structure

and transcription of human papillomavirus sequences
in cervical carcinoma cells. Nature 1985; 314:111.
31. Tommasino M, Adamczewski JP, Carlotti F, et al.

HPV16 E7 protein associates with the protein kinase
p33CDK2 and cyclin A. Oncogene 1993; 8:195.
32. Demers GW, Foster SA, Halbert CL, Galloway DA.

Growth arrest by induction of p53 in DNA damaged
keratinocytes is bypassed by human papillomavirus
16 E7. Proc Natl Acad Sci U S A 1994; 91:4382.
33. Brehm A, Nielsen SJ, Miska EA, et al. The E7

oncoprotein associates with Mi2 and histone
deacetylase activity to promote cell growth. EMBO J
1999; 18:2449.
34. Antinore MJ, Birrer MJ, Patel D, et al. The human

papillomavirus type 16 E7 gene product interacts with
and trans-activates the AP1 family of transcription
factors. EMBO J 1996; 15:1950.
35. Massimi P, Pim D, Banks L. Human papillomavirus

type 16 E7 binds to the conserved carboxy-terminal
region of the TATA box binding protein and this
contributes to E7 transforming activity. J Gen Virol
1997; 78 ( Pt 10):2607.
36. Jones DL, Alani RM, Münger K. The human

papillomavirus E7 oncoprotein can uncouple cellular
differentiation and proliferation in human keratinocytes
by abrogating p21Cip1-mediated inhibition of cdk2.
Genes Dev 1997; 11:2101.
37. Zerfass-Thome K, Zwerschke W, Mannhardt B, et al.

Inactivation of the cdk inhibitor p27KIP1 by the human
papillomavirus type 16 E7 oncoprotein. Oncogene
1996; 13:2323.
38. Francis DA, Schmid SI, Howley PM. Repression of the

integrated papillomavirus E6/E7 promoter is required
for growth suppression of cervical cancer cells. J Virol
2000; 74:2679.
39. Conley LJ, Ellerbrock TV, Bush TJ, et al. HIV-1

infection and risk of vulvovaginal and perianal
condylomata acuminata and intraepithelial neoplasia:
a prospective cohort study. Lancet 2002; 359:108.
40. Nyagol J, Leucci E, Onnis A, et al. The effects of HIV-

1 Tat protein on cell cycle during cervical
carcinogenesis. Cancer Biol Ther 2006; 5:684.
41. Tugizov SM, Herrera R, Chin-Hong P, et al. HIV-

associated disruption of mucosal epithelium facilitates
paracellular penetration by human papillomavirus.
Virology 2013; 446:378.
42. Chen Z, Kamath P, Zhang S, et al. Effectiveness of

three ribozymes for cleavage of an RNA transcript
from human papillomavirus type 18. Cancer Gene
Ther 1995; 2:263.
43. Bartsch D, Boye B, Baust C, et al. Retinoic acid-

mediated repression of human papillomavirus 18
transcription and different ligand regulation of the
retinoic acid receptor beta gene in non-tumorigenic
and tumorigenic HeLa hybrid cells. EMBO J 1992;
11:2283.
44. Braun L, Dürst M, Mikumo R, Gruppuso P. Differential

response of nontumorigenic and tumorigenic human
papillomavirus type 16-positive epithelial cells to
transforming growth factor beta 1. Cancer Res 1990;
50:7324.
45. Woodworth CD, Notario V, DiPaolo JA. Transforming

growth factors beta 1 and 2 transcriptionally regulate
human papillomavirus (HPV) type 16 early gene
expression in HPV-immortalized human genital
epithelial cells. J Virol 1990; 64:4767.
46. Khan MA, Tolleson WH, Gangemi JD, Pirisi L.

Inhibition of growth, transformation, and expression of
human papillomavirus type 16 E7 in human
keratinocytes by alpha interferons. J Virol 1993;
67:3396.
47. Soto U, Das BC, Lengert M, et al. Conversion of HPV

18 positive non-tumorigenic HeLa-fibroblast hybrids to
invasive growth involves loss of TNF-alpha mediated
repression of viral transcription and modification of the
AP-1 transcription complex. Oncogene 1999;
18:3187.
48. Storey A, Thomas M, Kalita A, et al. Role of a p53

polymorphism in the development of human
papillomavirus-associated cancer. Nature 1998;
393:229.
49. Chen TM, Pecoraro G, Defendi V. Genetic analysis of

in vitro progression of human papillomavirus-
transfected human cervical cells. Cancer Res 1993;
53:1167.
50. Palefsky JM. Cutaneous and genital HPV-associated

lesions in HIV-infected patients. Clin Dermatol 1997;
15:439.
51. Schiffman M, Wentzensen N, Wacholder S, et al.

Human papillomavirus testing in the prevention of
cervical cancer. J Natl Cancer Inst 2011; 103:368.
52. Ikenberg H, Bergeron C, Schmidt D, et al. Screening

for cervical cancer precursors with p16/Ki-67 dual-
stained cytology: results of the PALMS study. J Natl
Cancer Inst 2013; 105:1550.
Topic 8031 Version 26.0
Contributor Disclosures
Joel M Palefsky, MD Grant/Research/Clinical Trial Support:
Merck and Co [HPV vaccine (Gardasil-9)]. Consultant/Advisory
Boards: Antiva Biosciences [HPV therapeutics]; Vir Biotechnology
[HPV therapeutics]. Equity Ownership/Stock Options: Vir
Biotechnology [HPV therapeutics]; Virion Therapeutics [HPV
therapeutics]. Ross D Cranston, MD Grant/Research/Clinical
Trial Support: ABIVAX [HIV small-molecule therapeutics
(ABX464)]. Consultant/Advisory Boards (Spouse): ABIVAX [HIV
small-molecule therapeutics (ABX464)]; Aelix Therapeutics [HIV
therapeutic vaccine (HTI immunogen)]. Employment (Spouse):
Orion Biotechnology [Topical HIV microbicide (OB-002H)]. Don S
Dizon, MD, FACP Grant/Research/Clinical Trial Support: Bristol-
Myers Squibb [Ovarian cancer, cervical cancer (Nivolumab,
ipilimumab)]; Kazia [Ovarian cancer (Cantrixil)].
Consultant/Advisory Boards: AstraZeneca [Ovarian cancer
(Olaparib, durvalumab)]; Clovis Oncology [Ovarian cancer
(Rucaparib)]; Regeneron Pharmaceuticals [Squamous cell
carcinoma (Cemiplimab)]. David M Aboulafia, MD Nothing to
disclose Allyson Bloom, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the

editorial group. When found, these are addressed by vetting
through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately
referenced content is required of all authors and must conform to
UpToDate standards of evidence.
Conflict of interest policy

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20/1/2020 Virology of human papillomavirus infections and the link to cancer - UpToDate

Official reprint from UpToDate®

Virology of human papillomavirus

Literature review current through: Dec 2019. | This topic last

Human papillomavirus (HPV) is the most common sexually

involving the anogenital (cervical, vaginal, vulvar, penile,

Human papillomavirus (HPV) is a small deoxyribonucleic

HPV GENOTYPES AND RISK OF CANCER

HPV genotypes’ association with cancer risk varies, and is

Cervical cancer — There is a broad separation of HPV

Types 16 and 18 are the most commonly isolated HPV

Head and neck cancer — HPV infection is associated with

HPV types [4,5]. (See "Human papillomavirus-associated

Furthermore, the same sexual behaviors associated with

Anal cancer — HPV is also implicated in cancer of the

HPV 16 is the most commonly detected HPV type

● One study evaluated HPV genotypes in anal swab

A few of the more commonly isolated HPV types in the

● In a cohort of 346 men with HIV and 262 men without

This finding could reflect increased reporting of

related to failure of local mucosal immunity and

Penile cancer — HPV infection is also a risk factor for

The role of HPV infections in the etiology of epithelial

● HPV DNA is commonly present in anogenital

● Expression of the viral oncogenes E6 and E7 is

● The E6 and E7 gene products have transforming

● In cervical carcinoma cell lines, continued E6 and E7

● Epidemiologic studies indicate HPV infections as the

HPV proteins — The HPV genome encodes DNA

The two most important HPV proteins in the pathogenesis

intraepithelial neoplasia" and "Preinvasive and invasive

Role of p53 protein — In the normal cell, the p53 protein is

In contrast to the E6 protein, E7 protein sensitizes wild-type

Role of retinoblastoma protein — The Rb protein inhibits

In support of the importance of E7 in cellular transformation,

Other proteins — Other HPV proteins that may be

HIV infection — In addition to the effects of

promote HPV-associated oncogenesis at the molecular

Progression from immortalization to malignancy — In

● There is some evidence that a separate signaling

may be regulated in this manner via the retinoic acid

● Alterations in host cell DNA (eg, p53 mutations) may

These data suggest that intercellular cytokine-mediated

RISK FACTORS FOR HPV INFECTION

Genital HPV infections are considered to be spread by

Both primary (eg, the WHIM syndrome, described as Warts,

The detection of HPV is facilitated by recent advances in

clinical management of patients. HPV testing falls into three

● HPV DNA testing – HPV DNA testing was the first

● HPV ribonucleic acid (RNA) testing – HPV RNA

● Detection of cellular markers – Cellular marker

associated disease. The HPV E7 protein disrupts cell

There are several HPV DNA tests that are currently

the option of testing for HPV 16/18 specifically. The Aptima

Indications for testing — The role of HPV testing is in

● Cervical cancer screening – HPV testing as part of a

● Head and neck cancer – There is no role for HPV

● Anal cancer – The role for HPV testing in anal swab or

recommendations for anal HPV testing of populations

● Penile cancer – There are no clinically available tests

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from

INFORMATION FOR PATIENTS