Human Papilloma Virus – a primer

The human papilloma virus is a Baltimore Class I virus.  The genome is double stranded circular DNA surrounded by an icosahedral capsid. 

The virus infects basal epithelial cells (dividing cells) through microtears in the epidermis.  The virus interacts with a receptor, and likely a co-receptor and enters the cell through endocytosis.  As the viral capsid disassembles in the endosome, the viral DNA is transferred to the nucleus via an interaction with L2. 

“Following entry into basal epithelial cells, HPV genomes are established as autonomous replicating extrachromosomal elements [episomes] and a low-level of HPV expression occurs.  Upon differentiation of infected cells, productive replication and expression of capsid genes is induced resulting in the synthesis of progeny virions” [1].  See diagram below for an illustration of the virus life cycle in differentiating epithelial cells (click on the diagram to enlarge or go to http://www.unl.edu/virologycenter/research/P_Angeletti_Research.shtml).

Like other Class I viruses, there are 2 phases of viral gene expression, early and late.  Expression of the viral proteins is regulated as the infected cell differentiates and moves toward the epithelial surface.  Early in infection, the viral DNA is replicated during S-phase, along with the cellular DNA.  The E2 protein anchors the viral episome to mitotic chromosomes so that the episomes are segregated into newly dividing cells [2].  The viral genome is maintained in cells at a copy number between 50 and 100 copies per cell [3].

As the infected cells differentiate late proteins are expressed.  The late proteins encode for the virus capsid.  L1 and L2 self-assemble into viral particles and encapsidate viral genomes.  During terminal differentiation, the viral copy number is drastically increased and thousands of viral particles are produced per cell [3].  See diagram below or at http://www.clinsci.org/cs/110/0525/cs1100525f02.htm [2]. 

Most HPV infections self-resolve within 18 months – meaning they do not cause warts or cancer.  Virions are produced in the differentiated cells and leave as the dead cells are shedded (HPV does not cause cell lysis) [2].  Cancer results when “high-risk” type infections are not resolved and are maintained persistently for years or decades!  It is really the accummulation of secondary cellular mutations (due to E6 and E7 viral proteins preventing the cell from doing its job) that results in cancer [2]. 

There is a cool video at http://www.bris.ac.uk/biochemistry/gaston/hpv_life_cycle.htm that illustrates the differentiation of epithelial cells and the expression of HPV proteins and ultimately virions.  If it looks as if the animation has stalled, click on the blue button and the next step will begin.

HPV proteins:

E1 and E2 are required for viral DNA replication, as well as multiple host proteins.  E2 also plays a role in making sure the viral DNA moves into new cells during mitosis and acts as a transcription activator or repressor, controlling expression of other E genes, such as the viral oncogenes E6 and E7.  E6 and E7 are expressed early in the infection to promote cell division.  The dividing cells cary the HPV DNA with them [3].   E6 and E7 also associate with cellular tumor suppressor proteins, deregulating their normal function and drives cell proliferation.

E6 binds to and inhibits p53 (a cellular tumor suppressor protein).  The normal function of p53 is to repress the cell cycle if there is DNA damage [3].  Since this will not occur after a “high-risk” HPV infection, the cell can accumulate DNA mutations, which can in itself lead to cancer.  E6 can also activate telomerase, which allows the cell to replicate continuously [3].  E7 binds Rb, another tumor suppressor protein that helps control DNA replication and cell division [3].

Interestingly, as levels of E2 increase, E6/E7 are down-regulated.  This results in a loss of the cellular environment necessary for viral DNA replication.  This change in gene expression favors the production of HPV virions.  Once the infected cells reach terminal differentiation, the late genes L1 and L2 are expressed [3].  L1 and L2 are the capsid proteins.  These, as their name implies, are expressed in the second or late phase of the viral life cycle.  New virus particles are shed with the dead skin cells [3].

In latently infected cells, HPV DNA may be present but no differentiation-dependent synthesis of virions occurs.” [1]  HPV infection can be (1) cleared by the immune system, (2) persist and result in warts, or (3) persist and result in cancer.

What are warts?  Warts are caused by an increase in cell proliferation in the basal and suprabasal cellular compartments due to viral protein expression [2].  It takes about 4 weeks post-infection for warts to become visible [2].  Warts are considered non-life threatening and may resolve themselves (the immune system destroys the virus containing cells) or can be removed by chemicals at home or in the doctors office.

What is the difference between warts and cancer?  In cancer, cell proliferation in the suprabasal compartment is also increased due to expression of the viral oncogenes E6 and E7.  A main difference is that in cancer, normal terminal differentiation of the keratinocytes does not occur [2].  Not all types of HPV cause cancer, though they all express the same proteins (general function the same, but obviously there are differences).  Cancer-causing HPV types (16, 18, 31, 45) express “high-risk” forms of proteins E7 and E6.  These proteins have a more robust effect on cellular proteins than the “low-risk” versions.

It has also been shown that the HPV genome is integrated into the chromosome of cancer cells.  Interestingly, parts of the HPV genome are deleted during integration.  One of the most common deletions is that of the E2 gene region, resulting in deregulation of the E6 and E7 proteins.  In addition to the loss of cell cycle control, “high-risk” E6 and E7 gene expression results in a loss of DNA damage repair mechanisms.  Therefore, it is likely that the HPV-induced cancer is due to secondary mutations that accumulate during the virus infection. 

HPV and cervical cancer.  Cervical cancer is the second most common cancer in women worldwide!  Cervical cancer is only caused by infection with “high-risk” HPV types, such as HPV-16, -18, -31, or -45.  Cervical cancer is detected through annual PAP smear screening for women.  Women in monogamous relationships are advised to only get PAP smears every 2 – 3 years (but you better be SURE your relationship is monogamous since this is a sexually transmitted cancer).  The cancer can take 20+ years to show up!  The PAP smear looks for abnormal cell and intraepithelial neoplaisa lesions (so you can see how important it is for the nurse to get a good cell sample during your PAP smear!).  Molecular techniques are only used after an abnornal cytological diagnosis.

 [1] Stubenrauch and Laimins (1999)  Human papillomavirus life cycle: active and latent phases.  Seminar in Cancer Biology.  9 (6): 379-86.

[2] Doorbar (2006) Molecular biology of human papillomavirus infection and cervical cancer.  Clinical Science.  110: 525-541.

[3] Dr John Doorbar of the National Institute for Medical Research (2004) HPV Life Cycle. (Accessed 2-26-11)  http://www.bris.ac.uk/biochemistry/gaston/hpv_life_cycle.htm

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