Virology of human papillomavirus infections and the link to cancer

Authors
Joel M Palefsky, MD
Ross D Cranston, MD
Section Editors
Bruce J Dezube, MD
Don S Dizon, MD, FACP
Deputy Editor
Don S Dizon, MD, FACP
Disclosures: Joel M Palefsky, MD Grant/Research/Clinical Trial Support: Merck and Co [HPV infection
(Quadrivalent and nonavalent HPV vaccines)]; Hologic [HPV infection (HPV assay)]. Consultant/Advisory Boards:
Merck [HPV infection (Quadrivalent and nonavalent HPV vaccines)]; TheVax [HPV infection (therapeutic HPV
vaccine)]; Hera Therapeutics [HPV infection (HPV therapeutics)]. Ross D Cranston, MD Grant/Research/Clinical
Trial Support: Merck & Co [Inflammatory bowel disease/HPV (Gardasil)]. Bruce J Dezube, MD Nothing to
disclose. Don S Dizon, MD, FACP 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

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jun 2015. | This topic last updated: May 10, 2015.
INTRODUCTION Human papillomavirus (HPV) is the most common sexually transmitted
infection in the United States. The biology of these viruses has been studied extensively and its link
with malignancies is well established, specifically with cancers 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 "Epidemiology of human papillomavirus infections".)
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. (See "The life cycle, natural history, and immunology of human papillomaviruses".)
HPV GENOTYPES AND RISK OF CANCER There are numerous human papillomavirus (HPV)
genotypes, and their association with cancer risk varies. This is reviewed below.
Cervical cancer There is a broad separation of HPV genotypes 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 "Epidemiology of human papillomavirus infections", section on 'Cervical

cancer'.)
Head and neck cancer HPV infection is associated with some forms of oropharyngeal
squamous cell cancers, and 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 subtypes [4,5].
(See "Human papillomavirus associated head and neck cancer".)
Furthermore, the same high-risk sexual behaviors associated with risk for anogenital HPV-related
cancers may increase the risk of oropharyngeal squamous cell cancers in HPV-infected patients,
particularly in those patients co-infected with human immunodeficiency virus (HIV) [6]. This was
shown in one study of HIV-positive and HIV-negative men and women, which reported that oral
HPV infection was common (34 percent). In HIV-negative individuals, risk for HPV infection
increased with number of recent oro-genital or oro-anal sex partners. In HIV-positive individuals, 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 co-infection. As examples:
One study evaluated HPV genotypes in 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 HIV-positive and HIV-negative men.
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 HIV-infected and 262 HIV-negative men, multiple anal HPV types were
more common in the HIV-infected patients (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 HIV-positive individuals.
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 [12,13]. In one casecontrol study, 33 of 67 penile cancers were positive for HPV, of which 70 percent were HPV-16 [12].
Further, the risk of penile cancer among men reporting a history of condyloma acuminata was 5.9
times greater than that of men reporting no such history. (See "Carcinoma of the penis:
Epidemiology, risk factors, staging, and prognosis".)
MOLECULAR PATHOGENESIS The role of human papillomavirus (HPV) infections in the
etiology of epithelial cancers has been supported by the following observations [14]:

HPV DNA is commonly present in anogenital pre-cancer and invasive cancers, as well as
oral 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 growthregulating 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 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 [15,16].
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 [17]. 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 [18-21]. Following E6 binding of p53, p53 is degraded in the presence of E6-associated
protein [22]. This allows unchecked cellular cycling, and has an anti-apoptotic effect, permitting the
accumulation of chromosomal mutations without DNA repair [23,24]. 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 [14,25].
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 [26,27]. 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 [21,28]. 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 [29,30]. The interaction of E7 with Rb may permit cells with damaged DNA to
bypass the G1 growth arrest normally induced by wild-type p53 [31]. 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 [32]. 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 [33,34], and E7 proteins inactivate the cyclin-dependent kinase inhibitors p21(CIP1) and p27(KIP-1), which may lead to growth stimulation of HPV-infected cells [35,36].
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, regulation of E6 and E7 expression), and E5 (regulation of cell
growth) [15]. 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 [29]. 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 [37].
HIV infection In addition to the effects of immunosuppression, which promotes the persistence
of HPV infection, co-infection with human immunodeficiency virus (HIV) [38] may directly 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 [39].
(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 [40]. Oncogene transcription or
viral oncoprotein expression may be regulated in this manner via the retinoic acid receptor
[41], or by cytokines such as transforming growth factor beta [42,43], interferon-alpha [44], or
tumor necrosis factor-alpha [45].
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
[46]. Alternatively, genetically unmodified, high-risk, HPV-infected human cells may be blocked
from immortalization by intracellular control of viral oncoprotein function [47].
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 [14]. The
chromosomal instability that characterizes HPV infection may be one mechanism leading to these
genetic modifications.

RISK FACTORS FOR HPV INFECTION Genital human papillomavirus (HPV) infections are
considered to be spread by unprotected penetrative intercourse or close skin-to-skin physical
contact involving an infected area [48]. Digital/anal and digital/vaginal contact probably can also
spread the virus, as may fomites [48]. (See"Epidemiology of human papillomavirus infections".)
Both primary (eg, the WHIM syndrome, described as Warts, Hypogammaglobulinemia, Infections,
and Myelokathexis [a congenital disorder of the white blood cells that results in chronic leukopenia
and neutropenia]) and secondary immunodeficiency disorders (eg, human immunodeficiency virus
[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 'HPV'.)
DETECTING HPV The detection of human papillomavirus (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 [49]:
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 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 better
sensitivity and specificity than HPV DNA testing. This test has recently received US Food and
Drug Administration (FDA) approval for cervical HPV testing, as it significantly improves the
specificity of detecting 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. Although none of the p16-based tests are FDA-approved at this time, a large
study investigating the combination p16/Ki-67 dual-stained cytology has demonstrated
superior sensitivity and non-inferior specificity over Pap cytology to detect cervical HSIL
dysplasia [50].
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 16/18specifically.
Indications for testing The role of HPV testing is in evolution:

Cervical cancer HPV testing as part of a screening program for women is indicated in
specific populations either as a single test or as co-testing with Pap test, although primary
HPV screening may be effective in resource-poor areas. There is no role for HPV testing in
women with a diagnosis of cervical cancer, as it is not used for routine decision-making
regarding treatment. (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 as a screening test for
oropharyngeal cancer. However, given its prognostic implications for patients with
oropharyngeal carcinoma, testing is routinely recommended, specifically for patients with
squamous cell carcinoma, as it may impact the decision-making process. (See "Human
papillomavirus associated head and neck cancer", section on 'Clinicopathologic features'.)
Anal cancer The role for HPV testing for anal squamous intraepithelial lesions (SIL), a
precursor for anal cancer, is not clear. However, indirect evidence to screen high-risk
populations is available, including men who have sex with men who are also human
immunodeficiency virus (HIV)-infected. These data are discussed separately. (See "Anal
squamous intraepithelial lesions: Diagnosis, screening, prevention, and treatment", section on
'Screening for anal SIL'.)
Penile cancer We do not screen for HPV infection in men for the purpose of early 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 and diagnosis".)
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Beyond the Basics topics (see "Patient information: Human papillomavirus (HPV) vaccine
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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 appear to 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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