HPV in head and neck

Dr. Lakshmi
Mch Resident
 Introduction
• HNSCC- 20 % attributable to HPV
• OPSCC- 50 %
• 85% - HPV in lifetime
HPV
 HPV
• Double stranded DNA
• Circular
• 8000 base pairs
• 8kb size
• Non enveloped
• 6 early proteins- E1,2,4,5,6,7
• 2 Late proteins- L1,2
• Papillomaviridae
 Types of HPV
• Low risk-
• 1. HPV 6,11
• 2. benign – papilloma/warty

• High risk- HPV 16,18,33,35- cancer

 Natural H/o HPV
• Mostly cleared by immune system within 2
years
• Persistence of HPV
• 1. current smoking status
• 2. older age
• 3. lower CD4 count(HIV)
• 4. use of HAARt
• 5. Duration of HAART
 Risk factors for HPV
• 1. Younger
• 2. higher socioeconomic status
• 3. higher education
• 4. more lifetime sexual partners
• 5. white race
HPV genome
 HPV genome
• Early proteins
• E1,2- initiation of replication, maintenance of
viral genome
• E4- expressed late in infection, promotes
productive phase of virus
• E5- activate growth receptors
• E6,7- encode oncoproteins
 HPV genome
• E6
• A. Degrade p53
• B.activate telomerase in infected cell
prolonging lifespan of epithelial cells
• E7
• A. Inhibit Rb
• B. Disrupt normal cycle
Life cycle of HPV
 Life cycle of HPV; Early
• 1. infection of undifferentiated epithelial cells
in basal cell layer
• 2. Expression of E1,2
• 3. infected cells migrate to superficial layers
• 4. E6,7- modify cell for replication of viral
genome
 Life cycle of HPV; Late
• 1. cellular differentiation to granular epithelial
layer
• 2. L1, 2- major and minor capsid protein
production
• 3.L1- pentamers assemble with L2- viral
capsule- protect virus from environmental
insults
Lifecycle of HPV
E6,7 oncoproteins
E6,7 oncoproteins
 Cellular progression to dysplasia & CA
• Most HPV infections cleared by immune system /
latent infection of basal layer with low viral copy
• L1,2 along with E1,2- deleted with viral integration
• E2 disruption- Upregulation of E6,7
• E5- overexpression of EGFR- overexpression of proto
oncogenes, p21 repression- blocks apoptosis
• OVEREXPRESSION OF E6,7- maintains neoplastic
process
 Immune system & HPV
• 1. Humoral
• 2. Cellular
Humoral immune response
 Humoral immune response
• No major role in HPV
• Normally weak humoral response against L1
• High risk HPV- 30-50% - detectable Ab to L1
Cellular response
 Cellular response
• Important in HPV
• CD4, CD8 T cells
• But HPV in deep tonsillar crypts- evade
immune response
 Inhibitory effect of viral proteins
• HPV E5,7- Downregulates MHC -1
• Inhibit viral presentation to immune complex
• E6,7- reduce cytokines like IL-8- reduing
inflammation
 P16

• Tumor suppressor protein encoded

by CDKN2A gene (9p21.3)
• Prevents progression into S phase of cell cycle
– Inhibits cyclin D dependent protein kinases (CDK4 and
CDK6) therefore maintaining Rb in its
hypophosphorylated state which prevents its
dissociation from E2F transcription factor

• Protein expression often increased in aging cells-

cell death and apoptosis
P16
HPV vs Non HPV
 Clinical characteristics in HPV
• Oropharyngeal primary tumor
• Diagnosed at later stage
• Better survival
• Less likely tobacco/alcohol
• Neck nodes- Cystic
HPV detection
 Vaccines
• Quadrivalent- HPV 6,11,16,18- L1 capsid
protein
• Bivalent- HPV 16,18
Vaccines
 Immunotherapy
• Treatment of established disease
• Cellular immune system
• E6,7 – foreign viral proteins introduced for
developing immunity
 Immunomodulatory therapy
• Retinoic acid- Activation of retinoic acid
receptors by tissue hormone
• Cidofovir- induce apoptosis
 Molecular targets
• Cetuximab- EGFR suppression- E5
• HPV16,17- upregulate VEGF- Bevacizumab
• Celcoxib- COX2 overexpressed in HPV
THANK YOU