Virology of human papillomavirus infections and the link to cancer

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 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 — 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 "Epidemiology, staging, and clinical presentation of 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 human immunodeficiency virus (HIV) coinfection [6]. This was shown in one study of males and females with and without HIV, which reported that oral HPV infection was common (34 percent) [7]. 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 cell counts and increased number of lifetime sex partners. Individuals with HIV who are older than 50 years have a higher risk of oral and oropharyngeal cancer than the general population (standardized incidence ratio 1.7) [8].

Anal cancer — HPV is also implicated in cancer of the anus [1,9], and the spectrum of HPV types in the anal canal is similar to that described in the cervix [9].

HPV 16 is the most commonly detected HPV type associated with anal cancer [10-12]. 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 [9]. Despite this, the range of HPV types was similar in both males 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 [9].

●In a cohort of 346 males with HIV and 262 males 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 [9].

Penile cancer — HPV infection is also a risk factor for carcinoma of the penis and intraepithelial neoplasia [13-15]. (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 [16]:

●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 [17,18].

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 [19]. 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: Epidemiology, clinical presentation, diagnosis, screening, prevention, and treatment" and "Vaginal intraepithelial neoplasia" and "Preinvasive and invasive cervical neoplasia in patients with HIV infection".)

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 [20-23]. Following E6 binding of p53, p53 is degraded in the presence of E6-associated protein [24]. This allows unchecked cellular cycling, and has an anti-apoptotic effect, permitting the accumulation of chromosomal mutations without DNA repair [25,26]. 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 [16,27].

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 [28,29]. 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 [23,30]. 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 [31,32]. The interaction of E7 with Rb may permit cells with damaged DNA to bypass the G1 growth arrest normally induced by wild-type p53 [33]. 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 [34]. 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 [35,36], 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 [37,38].

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) [17]. 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 [31]. 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 [39].

HIV infection — In addition to the effects of immunosuppression, which promotes the persistence of HPV infection, coinfection with HIV [40] 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 [41]. 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 [42]. (See "Preinvasive and invasive cervical neoplasia in patients with HIV infection" 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 [43]. Oncogene transcription or viral oncoprotein expression may be regulated in this manner via the retinoic acid receptor [44], or by cytokines such as transforming growth factor beta [45,46], interferon-alpha [47], or tumor necrosis factor-alpha [48].

●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 [49]. Alternatively, genetically unmodified, high-risk HPV-infected human cells may be blocked from immortalization by intracellular control of viral oncoprotein function [50].

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 [16]. 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 [51]. Fomite, digital/anal, and digital/vaginal contact probably may also potentially spread the virus, although the evidence for this is not definitive [51]. (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 inborn errors of immunity", section on 'Human papillomavirus'.)

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 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. 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 10^th to 12^th 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

●Virology − 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.)

●HPV genotypes and risk of cancer − 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.)

●Molecular pathogenesis − 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.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ross D Cranston, MD, who contributed to an earlier version of this topic review.