Question

Describe the HPV virus lifecycle, how it is able to induce tumorigenesis, and why the virus does this (how does tumor formation “help” the virus?).

Answer 1

The epithelial cells are the sites of infection with HPV, and since HPV uses these epithelial cells as host and hence the replication of HPV is in tandem with the development of epithelial cells. The squamous epithelial cells develop into the stratified epithelium and the basal layer is where there is actively amplifying stem cells transiently. This is the place where the HPV virus prefers to enter using its viral capsid. It gains entry through minor cuts or abrasions or entry through the cervical region (between ecto and endo cervix). The viral capsid is made of two late proteins L1 and L2. The L1 of HPV binds to HSPG (heparin sulphate proteoglycans) receptor, this brings about a change within the virion and expresses the L2 protein and the N-terminal part of the L2 protein is exposed on the virion surface. This further is cleaved and and attaches to various receptors of the host cell like alpha 6 integrin, EGFR, laminins and few others. The type of HPV virus determines the mode of entry and the receptor to which it binds. The virus gains entry thereafter through endocytosis and reaches the cytoplasm from where it is transported to the nucleus using the tubulins during mitosis and establishes its replication. Now the regulatory proteins of HPV E1-E7 act to initiate and execute replication and produces episomal copies of the virus. This phase is initial multiplication of the virus is minimal and is only for it to set up viral genome maintenance. Thereafter the virus replicates by integrating with the host chromosome and then HPV is eventually multiplied when the cell replicates and spreads when the host cell divides into daughter cells. The infected cells move upward to the epithelial surface layers. during this migration event the viral replication peaks with the functioning of its late genes and this constitutes the vegetative phase of the virus, Once it recahes the upper epithelial layers the virions gets packed into capsids, and the progeny viruses are released, which in turn, each of it is capable of carrying out fresh infections. This constitutes the life cycle of HPV.

A prolonged infection which may be in terms of years by the HPV virus results in tumorigenesis. The viral regulatory proteins E6 and E7 acts continuously which stimulates the cell growth but inhibits differentiation and since it is integrated in the host chromosome drives in host chromosomal instability resulting in tumorigenesis of the host cell. The tumorigenesis becomes fully established when the HPV viruses attack the host cells p53 tumor suppressor proteins thereby inhibiting apoptosis of the infected and hence abnormal cells. This gives rise to severe complications wherein the mutations in cells go unchecked and up in accumulation of mutations, and thus most of the cervical cancers aggravate.This tumor formation hence helps the virus to produce consistently high numbers of copies of itself.  In less risk patients the virus maintains itself as warts.

Hope this helps, else please leave a comment for clarifications if any.