Mechanism of Infection

The pathogenesis of cervical cancer is initiated by HPV infection of the cervical epithelium during sexual intercourse. Virions penetrate the epithelium through microabrasions and invade the basal cells of stratified epithelia of the uterine cervical transformation zone, establishing their genomes as a stable, low copy number of viral episomes (50-100 genomes per cell) in an initial burst of replication (Fig. 3; see Color

Pathogenesis Human Papilloma Virus

Fig. 3 (Color Plate 4, following p. 50). HPV life cycle. The pathogenesis of cervical cancer is initiated by HPV infection of the cervical epithelium during sexual intercourse. Virions penetrate the epithelium through microabrasions and invade the basal cells of stratified epithelia. Initiation of replication is facilitated by interaction of E1 with E2. Because the virus replicates using the host machinery, it must force the keratinocytes into S phase, despite signals for terminal differentiation of the squamous epithelium. This is achieved by three viral oncoproteins: E5, E6, and E7 (see text). The action of these oncogenes and the upregulation of E1 and E2 in the upper layers of the squamous epithelium, provide for overreplication of the viral genome. E4 is the most abundantly expressed viral protein in HPV-infected epithelia. E4 is expressed later than E1, E2, E5, E6, and E7, but earlier than the capsid proteins and is believed to facilitate viral message translation and breakdown of the keratin networks to allow for virus release. L1 and L2 are virus coat proteins and are expressed late in the viral life cycle. The remaining E proteins with the exception of E4 are present throughout the life cycle.

Fig. 3 (Color Plate 4, following p. 50). HPV life cycle. The pathogenesis of cervical cancer is initiated by HPV infection of the cervical epithelium during sexual intercourse. Virions penetrate the epithelium through microabrasions and invade the basal cells of stratified epithelia. Initiation of replication is facilitated by interaction of E1 with E2. Because the virus replicates using the host machinery, it must force the keratinocytes into S phase, despite signals for terminal differentiation of the squamous epithelium. This is achieved by three viral oncoproteins: E5, E6, and E7 (see text). The action of these oncogenes and the upregulation of E1 and E2 in the upper layers of the squamous epithelium, provide for overreplication of the viral genome. E4 is the most abundantly expressed viral protein in HPV-infected epithelia. E4 is expressed later than E1, E2, E5, E6, and E7, but earlier than the capsid proteins and is believed to facilitate viral message translation and breakdown of the keratin networks to allow for virus release. L1 and L2 are virus coat proteins and are expressed late in the viral life cycle. The remaining E proteins with the exception of E4 are present throughout the life cycle.

Plate 4, following p. 50). The first step of papillomavirus infection is believed to be binding of major capsid protein L1 with the cell surface without involvement of minor capsid protein L2 (24). The nature of the primary surface receptor is controversial. Although, both cell surface heparin sulphate glycosaminoglycans and a6 integrin are sufficient to mediate interaction of particles with the cell surface, neither are necessary for infection in all cases (25). The minor capsid protein L2 plays a critical role in infection, but it functions after the initial binding of the virions with the cell surface (26). Its exact role is unclear, but L2 has been found to bind independently of L1 with the cell surface, to be processed by furin cleavage during infection (27) and to interact with syntaxin-18 (28) and actin (29) to facilitate passage of virions across the cytoplasm. The virions disintegrate after uptake, releasing the viral genome and L2 which enter into the nucleus together (30). L2 brings the viral genome to the ND-10 domain, which may facilitate early viral transcription and the initial burst of viral replication (31). The life cycle proceeds as described in the previous section.

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