The natural history of cervical HPV infection: unresolved issues

Key Points

  • The most frequently detected human papillomavirus (HPV) type at the time of diagnosis of squamous cell carcinoma (SCC) is HPV16, followed by HPV18. HPV18 is the type most strongly associated with adenocarcinoma of the cervix, which is increasing in incidence at the same time as the incidence of SCC is falling.

  • A bivalent HPV (types 16 and 18) and a quadrivalent HPV (types 6, 11, 16 and 18) vaccine are now being evaluated in phase III clinical trials, and have the potential to prevent about 70% of all cervical cancers. The quadrivalent HPV vaccine (Gardasil, Merck) has recently gained FDA and European Commission approval for use in women between the ages of 9–26.

  • Although most women will at some time be infected with HPV, very few will progress to invasive disease. The identification of more robust markers of disease progression requires a more complete understanding of the natural history of type-specific HPV infections.

  • It is unknown whether persistent HPV infections are characterized by the continuing detection of HPV, or by a state of viral latency during which the virus remains undetectable only to reappear later. A clearer understanding of these issues is essential for the effective implementation of screening strategies that include testing for HPV.

  • Integration of HPV into the host genome results in a loss of negative-feedback control of oncogene expression, following disruption of the viral regulatory early gene E2. Whether the integration event itself is crucial to carcinogenesis is the subject of continuing debate.

  • The prevalence of integrated forms varies with the infecting HPV type. Unlike HPV16, HPV18 integration seems virtually complete in women with cervical intraepithelial neoplasia grade 3 (CIN3) or invasive disease.

  • The association between viral load and cervical disease varies with the HPV type, the physical state of the virus and the heterogeneity of the cervical lesion. The complexity of these relationships indicates that a measurement of viral load is not clinically useful.

  • The concurrent or sequential detection of more than one HPV type is common. There is some evidence to indicate that the life cycles of different HPV types are not independent of each other, as has previously been assumed.

  • HPV oncogenes can activate the cellular methylation machinery. The pattern of HPV gene methylation varies with the viral life cycle, the presence of disease and possibly the HPV type.

  • Aberrant methylation of CpG islands in the promoter regions of tumour suppressor genes is one of several epigenetic changes that can contribute to carcinogenesis. The detection of these epigenetic changes in exfoliated cervical cells could improve the effectiveness of cervical screening programmes.


The identification of high-risk human papillomavirus (HPV) types as a necessary cause of cervical cancer offers the prospect of effective primary prevention and the possibility of improving the efficiency of cervical screening programmes. However, for these opportunities to be realized, a more complete understanding of the natural history of HPV infection, and its relationship to the development of epithelial abnormalities of the cervix, is required. We discuss areas of uncertainty, and their possible effect on disease prevention strategies.

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Figure 1: HPV-mediated progression to cervical cancer.
Figure 2: General patterns of infection.
Figure 3: Persistent HPV infection.


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We gratefully acknowledge the support of Cancer Research UK.

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Correspondence to Ciaran B. J. Woodman.

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Lawrence S. Young has a paid consultancy with Glaxo Smith Kline.

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Cervical cancer


Division of Cancer Studies,University of Birmingham



A malignant tumour originating in glandular tissue.

Cross-sectional study

A study examining the association between disease and exposure at one point in time (a prevalence study). The temporal sequence of cause and effect cannot be determined with this study design.


A piece of hereditary material that can exist as free, autonomously replicating DNA.

Cervical intraepithelial neoplasia

(CIN) A disease characterized by precancerous changes in, and confined to, the epithelial cells lining the cervix.


An epithelial abnormality in which the cells becomes disorganized, which is charac-terized by developmental changes in cell growth, shape and organization.

Natural history

The course of disease or infection from onset to resolution.


Inherited changes in gene expression resulting from altered chromatin structure or DNA modification rather than changes in DNA sequence.

Latent infection

The persistence of an infection in a host without symptoms and/or without being detectable.


A new occurrence of disease or infection in someone previously free of disease or infection.

Longitudinal study

A study in which subjects are followed over a period of time so that the temporal sequence of potential cause and effect can be established.


The classification of patients according to priority of need.

Squamous intraepithelial lesion

(SIL). A disease characterized by the abnormal growth of squamous cells on the surface of the cervix. It is classified cytologically as low-grade (LSIL) or high-grade (HSIL) according to how much of the cervix is affected and how abnormal the cells are.


The visual examination of the uterine cervix with a magnifying lens to detect abnormal cells.

Fragile site

A site on a chromosome that tends to break more often than other sites.

Insertional mutagenesis

The occurrence of a mutation that is caused by the introduction of foreign DNA sequences into a gene.


An epidermal cell that produces the protein keratin.

CpG island

A region of genomic DNA in which the frequency of the CG sequence is higher than in other regions.

DNA methyltransferase

An enzyme that transfers a methyl group to DNA. DNMT1 is the most abundant methyltransferase and is the main maintenance methyltransferase. DNMT3A and DNMT3B are the main de novo methyltransferases.

Pocket protein

The pocket protein family includes three proteins, RB (retinoblastoma), RBL1 (retinoblastoma-like 1) and RBL2. They have a crucial role in cell-cycle regulation through interaction with the E2F transcription factors.

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Woodman, C., Collins, S. & Young, L. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer 7, 11–22 (2007).

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