Virology of human papillomavirus infections and the link to cancer

Virology of human papillomavirus infections and the link to cancer

Authors

Joel M Palefsky, MD

Ross D Cranston, MD

Section Editor

Bruce J Dezube, MD

Deputy Editor

Don S Dizon, MD, FACP

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2013. | This topic last updated: sep 28, 2012.

INTRODUCTION — Human papillomavirus (HPV) is the most commonly diagnosed sexually transmitted infection in the United States. It is associated with condyloma acuminata, anogenital (cervical, vaginal, vulval, penile, anal) squamous intraepithelial lesions and malignancy, and head and neck cancer.

The biology of these viruses has been studied extensively because of this link with malignancies. 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 — 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.

ASSOCIATION WITH MALIGNANCY — HPV genotypes can be broadly split into “high-risk” (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68) and “low-risk” (6, 11, 40, 42, 43, 44, 53, 54, 61, 72, 73 and 81) based upon their phenotypic association with the development of cervical cancer. 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'.)

HPV is also implicated in cancer of the anus [1,4]. The spectrum of HPV types in the anal canal is similar to that described in the cervix and is associated with the same risk phenotypes [4]. HPV 16 is also the most commonly detected HPV type associated with anal cancer [5-7]. Using PCR typing techniques, one group has isolated 29 individual HPV types and 10 HPV groups from the anal canal of men who have sex with men (MSM), both with and without HIV infection [4]. The range of HPV types is similar in the 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.

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 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). This is probably related to failure of local mucosal immunity and reactivation of HPV to reach detectable levels [4].

HPV infection is also a risk factor for carcinoma of the penis [8,9]. In one case-control study, 33 of 67 penile cancers were positive for HPV, of which 70 percent were HPV-16 [8]. 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".)

In addition, some oropharyngeal squamous cell cancers appear to be linked to HPV infection. There is an approximately two- to threefold increased risk for cancers of the oral cavity and oropharynx in patients infected with high-risk (oncogenic) HPV subtypes. Furthermore, the same high-risk sexual behaviors that increase the risk for anogenital HPV related cancers also increase the risk of oropharyngeal squamous cell cancers in HPV infected patients [10]. (See "Human papillomavirus associated head and neck cancer".)

MOLECULAR PATHOGENESIS — The role of HPV infections in the etiology of epithelial cancers has been supported by the following observations [11]:

 HPV DNA is commonly present in anogenital and oral cancers and precancers

 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

The HPV genome encodes DNA sequences for six early (E) proteins associated with viral gene regulation and cell transformation, two late (L) proteins which form the shell of the virus, and a region of regulatory DNA sequences known as the long control region or upstream regulatory region [12,13].

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 [14]. 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 intraepithelial neoplasia: 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

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