The Character of HPV

The papillomaviruses are genetically stable, small, DNA-based, non-enveloped viruses. They belong to the Papillomaviridae family of viruses, which are specific to the host species and have been detected in many animals and humans (Burd 2003). Some types of human papillomavirus (HPV) infect the genital mucosa, and these can be classified as either oncogenic or low-risk according to their pathogenic effects on the human host (Burd 2003; de Villiers et al 2004; Muñoz et al 2003).

• Over 200 papillomaviruses have been described (Burd 2003; de Villiers et al 2004)
  
• Approximately 100 types have been identified as specific to humans (de Villiers et al 2004)
  
• At least 30-40 human types of papillomavirus are known to infect the genital mucosa, and thus form part of the Alpha-papillomavirus genus (Burd 2003; de Villiers et al 2004; Muñoz et al 2003)
  
• The HPVs that infect the genital mucosa can be classified as either oncogenic or low-risk (Burd 2003; de Villiers et al 2004; Muñoz et al 2003)
  
• HPV 16 and 18 are the most prevalent oncogenic types worldwide, found in more than 70% of cervical cancers (Clifford et al 2005b; Muñoz et al 2003; Muñoz et al 2004)

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The HPV genome usually contains between eight and ten genes, depending on the HPV type, which are divided into early and late groups according to their function (Prendiville and Davies 2004b).

HPV typically infects the basal cells. The early genes encode the proteins necessary for the replication of the virus in the basal, parabasal and intermediate cells, whilst the late genes encode in the superficial cells the proteins that give HPV its structure.

HPV 16 is the most important oncogenic type found in cervical cancers in all regions studied to date, followed by HPV 18. Regional differences in the prevalence of HPV types do exist. For example, HPV 16 DNA is found in 67.6% of cervical cancers in Northern Africa as compared to 47.7% in Sub-Saharan Africa. HPV 18 DNA is found in 25.7% of cervical cancers in South Asia but only 12.6% in Central/South America (Muñoz et al 2004).

HPV is a DNA-based and highly stable virus, with a well-understood genetic classification.

HPV genome

The HPV genome contains approximately 8000 base pairs (Danos et al 1982) and is divided into three functional regions: non-coding, early and late (Prendiville and Davies 2004b).

• Early region: This contains the open reading frame protein-coding sequences E1, E2, E4, E5, E6, and E7. These are expressed first in the viral life cycle, only in the basal, parabasal and intermediate cells, and are involved in viral replication (E1, 2, 4 and 5) and promoting host cell division, which can lead to oncogenesis (E6 and 7).
  
• Late region: This region encodes the L1 and L2 structural proteins, which are expressed later in the viral life cycle, only in the superficial cells.
  
• Non-coding region: Also known as the long control region (LCR) or upper regulatory region (URR), this consists of 400–1000 base pairs. This region contains the promoter, enhancer and silencer sequences, which regulate the replication of the viral DNA.

(Reference: Adapted from: Prendiville & Davies 2004b)

HPV structure

The structure of the outer capsule of the HPV virus is determined by the capsid proteins, which are encoded by the late region of the HPV genome. The HPV virus is highly stable, and it has no envelope.

• L1, the major structural capsid protein, is triangular. Five L1 capsid proteins join to form a pentamer, and 72 pentamers form the spherical L1 protein shell of the HPV capsid (Baker et al 1991).
  
• The minor structural protein, L2, is thought to play a supportive role between the 72 L1 pentamers. Between 7 and 20 copies of the L2 protein are found in each virion capsid (Sapp et al 1995).

The structural proteins of HPV have evolved to allow easy entry into host cells via cell surface receptors present on the human basal cell (Evander et al 1997; Giroglou et al 2001). The L1 structural proteins are recognised as foreign and targeted by the T-helper cells, as the host immune system attempts to prevent infection (Luxton and Shepherd 2001).

The Geographical Distribution of HPV Types

There are geographical differences in the distribution of HPV types. A pooled analysis of data from 3607 women in 25 countries, with histologically confirmed cervical cancer, revealed that HPV 16 was the most common type, followed by HPV 18 in all regions (Muñoz et al 2004).

(Reference: Muñoz et al 2004)

HPV 16 is the most common oncogenic type found in women without cervical abnormalities. A subsequent study that analysed HPV type distribution in 15,613 women without cytological abnormalities from 11 countries, found that HPV 16 was the most common oncogenic HPV type in all countries (except Sub-Saharan Africa, where HPV 35 was equally prevalent). Women with HPV in Europe and South America are significantly more likely to be infected with HPV 16 than those in sub-Saharan Africa (Clifford et al 2005a).

Both HPV 16 and 18 are more common in women with cervical cancer than in women with an oncogenic HPV infection but without evidence of cervical abnormalities. This suggests that infection with HPV 16 and 18 is more likely to progress to cervical cancer than infection with other oncogenic HPV types (Clifford et al 2005b).


HPV phylogenetics

Papillomaviruses are classified according to sequence differences in the L1 capsid gene, which is genetically stable and therefore particularly well conserved among all members of the papillomavirus family (de Villiers et al 2004). Over 200 papillomavirus types have been described, around 100 of which infect humans and are therefore classified as HPV (Burd 2003; de Villiers et al 2004).

• HPV genera <60% homology across the L1 gene
  
• HPV species 60-70% homology across the L1 gene
  
• HPV types 71-89% homology across the L1 gene
  
• Subtypes of an HPV type 90-98% homology across the L1 gene
  
• Variants of an HPV subtype >98% homology across the L1 gene.

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(Reference: Adapted from: Burns and Maitland 2005; Harper et al 2004)

The mucosal types of HPV, which include the oncogenic types, belong to the alpha-papillomavirus genus. Both oncogenic and low-risk HPV types can be found within this genus, but they generally form distinct species. For example, the oncogenic HPV types 16, 31 and 52 fall into species 9, whilst oncogenic HPV 18 and 45 fall into species 7. Similarly, low-risk HPV types tend to be most closely related to other low-risk types. For example HPV 6 and 11, which can both cause anogenital warts, are closely related (species 10) (de Villiers et al 2004).

The prevalence of HPV varies between types. HPV 16 and 18 are the most prevalent oncogenic types, and together they are found in more than 70% of cervical cancers worldwide (Clifford et al 2005b; Muñoz et al 2003; Muñoz et al 2004). HPV 31, 45 and 52 are also oncogenic types (de Villiers et al 2004), and are found in a further 11.9% of cervical cancers (Muñoz et al 2004). HPV types 6 and 11 are both low-risk types and are found in 90% of anogenital warts (von Krogh 2001)

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