HPV Infection - Path to Malignancy
With the large amount of work behind the development of the HPV vaccines, there has been an improved understanding of how the human papilloma virus (HPV) infects and sets off malignant changes in the squamous epithelium. About 0.5million of cancers are attributed to HPV infection each year in the world. Majority of this HPV derived cancers are cervical cancers. HPV infection also causes cancers of the vulva, vagina, penis and oro-pharynx.
The HPV is a simple, non-enveloped double-stranded DNA virus. It is a very common virus with more than 100 sub-types identified. About 30-40 HPV types that infect the genital area of women and men, and they are grouped into the low risk types that cause genital warts (HPV 6, 11) and the high risk types that cause cancer (HPV 16, 18). The infectious cycle of HPV involve only squamous epithelia (commonly the cervix, vagina, vulva, penis) and it does not have a viraemic phase. The HPV genome of 8000 base pairs (that code for 8 genes/proteins) is sealed within a protein coat. The genes are grouped into early genes (E1-E7, which control the transcription of viral genes and replication of viral DNA) and the late genes (L1 and L2, which encodes the viral capsid coat). In the high risk HPV types, the E6 and E7 genes may become up-regulated and unlinked to the host cell replication mechanism, thereby transforming the host cell and giving it malignant potential.
HPV infection is a sexually transmitted infection. Most women become exposed to and infected with HPV shortly after initiating coital activity. The infection is confined to the squamous epithelium – i.e. there is no viraemia and the HPV does not cause cell death (as its host cell is destined to die as the virus replicates). The HPV targets the immature basal cells of the epithelium. To infect the cells, there must first be micro-trauma to expose the basal cells through crevices down the upper layers of keratinocytes. The HPV is attached onto the exposed basement membrane by heparin sulphate proteoglycans, which facilitate the entry of HPV into the basal cells. The viral DNA replicates within the host’s genome. When first infected, the HPV may reside in the basal cell host for a variable period of time – weeks to years. At a particular point, the virus may be kick-started to replicate within the host. At the lower layers of dividing cells (basal and parabasal cells), the virus and the cell replicate together, and only the E genes are expressed with small amount of viral protein made. At the middle layers of differentiated keratinocytes, viral DNA amplification occurs in the non-dividing cells, and both the E and L genes are expressed. In the mature keratinocytes, the encoded viral proteins organized into infectious virions and large numbers are assembled being released when the cell desquamate. At this stage, examination of the cervix may show cytological features of HPV infection, colposcopic evidence of CIN or positive HPV DNA.
Types of HPV Infection
This stage of viral shedding and infection can last a variable period. Eventually the woman develops a cell mediated immune response as the mobilized killer cells arrive to clear the HPV, allowing the lesion to regress. About the same time, sero-conversion occurs when antibody to the HPV-type specific protein (L1) is formed. On the whole, 80-90% of women generates a strong enough immune response to overcome the HPV infection and achieved a sustained clinical remission and become HPV DNA negative. The immune response failed to eradicate the HPV in the remaining 10-20%, and the women remain HPV DNA positive, entering into phase of viral persistence that may last for months and years. Clinically, this latter group is represented by persistent CIN2/3 or recurrent CIN. In some women with persistent HPV infection (>6months), the viral gene expression becomes unlinked to the differentiation of the host basal cells, resulting in over-expression of E6 and E7 proteins. This disrupted the normal cell cycle regulation and the apotoptic mechanism, leading to increased uncontrolled viral replication. Such deranged nuclear activity encouraged aberrant mitotic events and aneuploidy in the host cell, which are critical events culminating in malignant progression.
Therefore, the non invasive HPV associated cervical esions may be represented as 2 distinct entities.