Background to HPV

HPV replication

 
Papillomaviruses are small non-envelopped, double stranded DNA viruses. Human papillomaviruses have a genome of only 8kb, but about 100 different HPV types have been described to date.  Approximately 30 HPV types have been isolated from the human anogenital epithelium (cervix, vagina, vulva, rectum and penis) and from mucosal tissue (mucogenital types).  Mucogenital HPV types are often classified as low-risk or high-risk depending upon their association with lesion types.  Low-risk viral types are associated with low-grade lesions such as condylomas, but not with cancer.  High-risk viral types are associated with high-grade cervical lesions and cancer.


The genetic organization of papillomaviruses is relatively simple since the viral genome encodes only 8 proteins. E1 and E2 are the only viral proteins involved in viral DNA replication since these viruses rely on the host’s cellular replication machinery.  The viral cycle is closely linked to the differentiation of epithelial cells.  HPV infect stem cells of the basal layer of the epithelium via micro-lesions.  The early genes E1 and E2 are expressed in the basal layer to support replication of the viral genome as an episome to a 50-100 copies by cell. The infected basal cells divide into two daughter-cells in which the viral genome is equally distributed. One cell remains in the basal layer and, as a stem cell, keeps on dividing, thus creating a latent viral reservoir. The other (suprabasal) cell migrates to the superior layers of the epithelium, starting the differentiation process (during 21 days for the skin). The HPV production phase occurs in differentiated epithelial cells with a massive vegetative viral replication (up to 10 000 viral genomes/cell), late viral gene expression, virion production and dissemination by natural desquamation of the corneous layer cells.


E1 and E2 are multifunctional proteins able to form a complex and to specifically bind viral DNA to control transcription and replication:

  • E1 binds weakly, but specifically to viral DNA and displays ATPase and helicase activities necessary for initiation of viral DNA replication,
  • E2 is a transcription factor also involved in viral replication. By strongly binding to the viral replication origin (Ori) and interacting with E1, E2 stabilizes the binding of E1 to the replication origin, inhibits the formation of nucleosome and recruits cellular factors required for viral DNA replication.

Since the generation of HPV viral particles is restricted to differentiated cells, the basal layer cells are not lysed by virion production and keep on proliferating. This latent reservoir explains why HPV infection in the basal layer can persist for years and why such a high recurrence rate is observed with current treatments.  Since maintenance of viral DNA in the basal layer constitues a reservoir, Anaconda is targeting basal viral DNA replication for which early viral proteins E1 and E2 are the only necessary viral components.

 

HPV drug targets
 

Several molecular activities can be targeted in order to specifically inhibit viral DNA replication including the enzymatic activities of E1, E1 or E2 binding to viral DNA, E1/E2 protein:protein interaction, E1 hexamer formation, E2 post-translational modifications, or viral DNA segregation during cell division.

 

 

Most of these molecular targets have already been addressed by several pharmaceutical companies who subsequently failed to identify a potent and specific inhibitor. Anaconda is targeting the E1/E2 interaction since disruption of this interaction leads to inhibition of viral DNA replication.


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