Papillomaviruses

Simply. what are three ways HPV can establish chronic infection?

• Immune avoidance

• Immune evasion

• Tissue regeneration / remodeling

How does HPV avoid the immune system?

• Infection occurs rapidly after penetration of epithelial basal layer, limits its visibility

• Can restrict viral gene expression until after inflammation, prevents presentation whilst T cells are highly active in that area

• Basal cell reservoir

How does HPV remodel / regenerate tissue

• E5 associates with EGFR (RTK), ligand-independent proliferation signals

• E6 represses p53 and inhibits differentiation by suppressing NOTCH signaling (want to be more stem-like to maintain high proliferation)

• E7 drives bypass of G1/S checkpoint by sequestering Rb (cannot sequester E2F)

How does HPV evade the immune system

• E5 reduces MHC expression

• E6 disrupts interferon signalling

• E7 inhibits transcription of STAT, IFN TFs and proteins involved in MHC antigen presentation

Capsid shape of papillomaviruses

• Icosahedral

Baltimore classification of papillomaviruses

• Group I (dsDNA - viral DNA alone is infectious)

Describe how papillomaviruses can modify the host cell via cell transformation

• Induce cell metabolism and proliferation before synthesis of the new virus to increase the NTP pool

• Sometimes even if viral replication fails, cell proliferation signals continue

  Most notable in strains 16 and 18 of HPV

• Cell now exhibits uncontrolled growth and failure to respond to contact inhibition

Describe normal epithelial tissue homeostasis

• Balances proliferation and differentiation

• Basal epithelia divide until they reach a density that triggers them to commit to differentiation

• Pushed out of basal layer

• Programmed terminal differentiation until they reach the upper epithelium

• Produce keratin (mechanical strength) and lipids (waterproof)

Describe the impact of low-risk HPV types on epithelial homeostasis

• Preferentially chronically retained in basal layer

• Disrupt Notch signaling pathway to delay basal cell differentiation

• Epithelia remain more stem-like and retain replication ability as pushed higher in epithelia

Describe the impact of high-risk HPV types on eptihelial homeostasis

• Lack precise regulation, but Notch-mediated commitment to differentiation delayed further even as cells divide further up the epithelium

• Immune response to undifferentiated cells reaching the upper epithelium repressed by E5/6/7, which also assists HPV genome persistence and accumulation of genetic errors

• Chronic infection in whole epithelium

What facilitates HPV persistance?

• Can express their genes at very low levels in the lower epithelial layers

• E6 reduces E-cadherin levels on keratin surface which limits retention of Langerhans cells in the infected area

• Still mostly cleared in under 18months due to T-cell response