Gynecologic Oncology Consult

Understanding the human papillomavirus


 

Human papillomavirus (HPV) is the most prevalent sexually transmitted disease globally. It is causally related to the development of several malignancies, including cervical, anal, and oropharyngeal ones, because of its integration and dysregulation of the genome of infected cells. Fortunately, vaccination is available to prevent development of HPV-related diseases. Understanding this virus, its carcinogenic role, and the importance of prevention through vaccination are critically important for ob.gyns. This column reviews the fundamentals of HPV biology, epidemiology, and carcinogenesis.

Dr. Emma C. Rossi

Dr. Emma C. Rossi

Viral anatomy

HPV are members of the A genus of the family Papovaviridae. They contain between 7,800 and 7,900 base pairs. They are nonenveloped, double-stranded DNA viruses with a circular structure. The viral DNA is contained within an icosahedral capsid that measures 45 nm-55 nm. The HPV genome has three critical regions: the long control region, otherwise known as the upstream regulatory region; the early region; and the late region.1

Capsid proteins are similar between groups. Therefore, HPV are categorized into “types” and “subtypes” based on the extent of DNA similarity. There are more than 100 types of HPV in humans.2 The type of HPV is determined by the gene sequences of E6/E7 and L1 and must show more than 10% difference between types. The gene sequences between different subtypes differ by 2%-5%.

National Cancer Institute

Epidemiology of HPV infection

HPV are widely distributed among mammalian species but are species specific. Their tissue affinity varies by type. HPV types 1, 2, and 4 cause common or plantar warts. HPV types 6 and 11 cause condyloma acuminata (genital warts) and low grade dysplasia. HPV types 16 and 18 – in addition to 31 and 52 – are of particular interest to oncologists because they are associated with lower genital tract high grade dysplasia and invasive carcinoma. Infection with HPV 16 is present in about half of invasive cervical cancers, with HPV type 18 present in 20% of cervical cancers. Adenocarcinomas of the cervix are more commonly associated with HPV 18. Anal cancer and oropharyngeal cancer are more commonly associated with HPV 16.3

HPV infections are acquired through cutaneous touching (including hand to genital) and HPV positivity is most commonly present within the first 10 years after sexual debut.4 However, most individuals who acquire HPV do so as a transient infection, which is cleared without sequelae. Those who fail to rapidly clear HPV infection, and in whom it becomes chronic, face an increasing risk of development of dysplasia and invasive carcinoma. The incidence of HPV infection increases again at menopause, but, for these older women, the new finding of HPV detection may be related to reactivation of an earlier infection rather than exclusively new exposure to the virus.5

Diagnosis and testing

HPV infection can be detected through DNA testing, RNA testing, and cellular markers.6

HPV DNA testing was the original form of testing offered. It improved the sensitivity over cytology alone in the detection of precursors to malignancy but had relatively poor specificity, resulting in a high false positive rate and unnecessary referral to colposcopy. The various tests approved by the Food and Drug Administration – Hybrid Capture 2 (HC2), Cervista, and Cobas 4800 – differ in the number and nature of HPV types that they detect.

HPV RNA testing has developed and involves measuring the expression of E6 and E7 RNA. This testing is FDA approved and has the potential to improve upon the specificity of DNA testing procedures by decreasing false positives.

Measurement of cellular markers is currently considered experimental/exploratory and is not yet FDA approved for diagnostic purposes in screening or confirmation of HPV infection or coexisting dysplasia. It involves measuring the downstream cellular targets (such as p16) of E6 or E7 activity.

The mechanism of carcinogenesis

The early region of the HPV genome is downstream from the upstream regulatory region. It codes for proteins involved in viral infection and replication. The two most important genes in the early region are E6 and E7. When integrated into the human genome of the lower genital tract cell, the viral genes E6 and E7 negatively interfere with cell cycle control and mechanisms to halt dysregulation.7

E6 and E7 are considered oncogenes because they cause loss of function of the critical tumor suppressor proteins p53 and the retinoblastoma protein. The p53 protein is typically responsible for controlling cell cycling through the G0/G1 to S phases. It involves stalling cellular mitosis in order to facilitate DNA repair mechanisms in the case of damaged cells, thereby preventing replication of DNA aberrations. The retinoblastoma protein also functions to inhibit cells that have acquired DNA damage from cycling and induces apoptosis in DNA damaged cells. When protein products of E6 and E7 negatively interact with these two tumor suppressor proteins they overcome the cell’s safeguard arrest response.

In the presence of other carcinogens, such as products of tobacco exposure, the increased DNA damage sustained by the genital tract cell is allowed to go relatively unchecked by the HPV coinfection, which has disabled tumor suppressor function. This facilitates immortality of the damaged cell, amplification of additional DNA mutations, and unchecked cellular growth and dysplastic transformation. E6 and E7 are strongly expressed in invasive genital tract lesions to support its important role in carcinogenesis.

HIV coinfection is another factor that promotes carcinogenesis following HPV infection because it inhibits clearance of the virus through T-cell mediated immunosuppression and directly enhances expression of E6 and E7 proteins in the HIV and HPV coinfected cell.8 For these reasons, HIV-positive women are less likely to clear HPV infection and more likely to develop high grade dysplasia or invasive carcinomas.

Prevention and vaccination

HPV vaccinations utilize virus-like particles (VLPs). These VLPs are capsid particles generated from the L1 region of the HPV DNA. The capsid proteins coded for by L1 are highly immunogenic. VLPs are recombinant proteins created in benign biologic systems (such as yeast) and contain no inner DNA core (effectively empty viral capsids) and therefore are not infectious. The L1 gene is incorporated into a plasmid, which is inserted into the nucleus of a eukaryotic cell. Transcription and translation of the L1 gene takes place, creating capsid proteins that self-assemble into VLPs. These VLPs are retrieved and inoculated into candidate patients to illicit an immune response.

Quadrivalent, nine-valent, and bivalent vaccines are available worldwide. However, only the nine-valent vaccine – protective against types 6, 11, 16, 18, 31, 33, 45, 52, and 58 – is available in the United States. This theoretically provides more comprehensive coverage against cervical cancer–causing HPV types, as 70% of cervical cancer is attributable to HPV 16 and 18, but an additional 20% is attributable to HPV 31, 33, 45, 52, and 58. This vaccine also provides protection against the HPV strains that cause genital warts and low-grade dysplastic changes.9

HPV, in most instances, is a transient virus with no sequelae. However, if not cleared from the cells of the lower genital tract, anus, or oropharynx it can result in the breakdown of cellular correction strategies and culminate in invasive carcinoma. Fortunately, highly effective and safe vaccinations are available and should be broadly prescribed.

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported having no relevant financial disclosures.

References

1. Cancer Epidemiol Biomarkers Prev. 1995 Jun;4(4):415-28.

2. Gynecol Oncol. 2011 Apr;121(1):32-42.

3. Cancer Epidemiol Biomarkers Prev. 2008 Jul;17(7):1611-22.

4. JAMA. 2007 Feb 28;297(8):813-9.

5. J Infect Dis. 2013; 207(2): 272-80.

6. J Natl Cancer Inst. 2011 Mar 2;103(5):368-83.

7. J Natl Cancer Inst. 2000 May 3;92(9):690-8.

8. Lancet. 2002 Jan 12;359(9301):108-13.

9. Obstet Gynecol 2017;129:e173–8.

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