Human Papillomavirus

What lifestyle does HPV have?

Persistent-Latent

What are the two main papillomavirus tropisms?

Mucosal (HPV!)

Cutaneous (common warts)

What are the two main types o HPV that cause cervical cancer?

HPV16 and HPV18

What is the structure of HPV?

Icosahedral, non-enveloped dsDNA virus

What are the four stages of HPV infections regarding histopathology? Which stages can be cleared by the immune system?

Normal (can be cleared)

CIN 1 (can be cleared)

CIN 2/3

Cancer

Treatment of cervical abnormality/cancer

Mechanical removal of damaged tissue

Radiotherapy

Chemotherapy

Immunotherapy

No anti-virals!

What are the three main HPV vaccines?

Cervarix (16 and 18)

Gardasil (plus two strains)

Gardasil 9 (plus 7 strains)

What proteins are in the capsid?

L1 and L2

What are the steps for early stage infection (until in nucleus)

Binds to primary receptor (heparin sulphate)

Conformational change of L1/L2

Binds secondary receptors

Endocytosed

Endosome acidifies

Virus uncoated

L2/vDNA transported into the nucleus

What cells are the primary target for HPV

Epithelial basal cells

Life cycle linked to cell differentiation—DNA replication and early phase genes strongest before cell differentiated, get late phase and virion assembly when cells more differentiated

What kind of DNA replication does HPV use?

Theta type replication, then likely rolling circle replication

What are the three phases of DNA amplification?

Initial (low level, cell not differentiated)

Maintenance

Vegetative (cells more differentiated, massive amount of copies produced)

How does HPV bypass not having its own DNA polymerase

E1/E2 complex binds to origin of replication—E1 is a helicase that unwinds the DNA but needs E2 to bind better

Once unwound cellular DNA polymerase recruited and attaches

What is E2’s role regarding longevity of infection?

It can bind to both HPV and host chromosome, meaning it stays in daughter cells

What is the main issue for HPV with replication in highly differentiated cells and how does it deal with it?

Very little replication—very little DNA polymerase to use

Drive cell into S phase—E6 blocks p53 and E7 blocks pRb

How does inhibiting p53 and pRb help HPV?

p53 senses abnormal DNA, leads to apoptosis

pRb prevents E2F from allowing cell to be in S phase

What is an important transcriptional repressor of early promoter?

E2

How does alterative splicing work?

Late transcripts—without E6/E7, with L1/L2

Early transcripts—With E6/E7, without L1/L2

How is HPV mRNA splicing regulated?

Viral cis-RNA elements and cellular trans-factors

How does virion assembly work?

L1 monomers made into pentamers, each pentamer has 1 L2 in the middle

Makes up virion

What protein is used for the vaccine?

L1

What does E4 do?

Helps virus egress by reorganising keratin network

What are the two overarching strategies for persistent infection?

Less antigen presentation (restrict until in differentiated cell)

Repress immune response induction

How can HPV lead to cancer?

Can get dysregulated expression of E6 and E7

Get fails in cell cycle arrest leading to mutation accumulation