HPV INFECTION :basic virology,life cycle. Risk factors, types of HPV, transmission of infection. Pathogenesis and outcomes of HPV infection Manifestations: Condyloma acuminatum Diagnosis HPV triage strategy and prevention

1. Pooja Sanalkumar

2. Basic virology
 Papovaviridae family
 Double stranded DNA virus with a protein capsid.
 Infects human squamous/ metaplastic epithelial cells.
 130 genetically distinct HPV types, of which 30 – 40 primarily infects
lower anogenital region.

3. Life cycle
 Six EARLY ‘E’ genes govern functions early in viral life cycle,
including DNA maintenance, replication & transcription -
Expressed in lower epithelial layers.
 2 LATE genes encode major L1 & minor L2 capsid proteins –
expressed in superficial layers.
 Required to form a new, infectious viral particle.
 HPV gene expression occurs in synchrony with epithelial
differentiation.

4. Life cycle
 Non-lytic virus.
 Infectiousness depends on normal desquamation of infected
epithelial cells.
 New infection is initiated when L1 & L2
capsid proteins bind to epithelial basement
membrane & permits entry of HPV viral
particles into new host cells.

6. Risk factors
 Early age of sexual intercourse
 Multiple sexual partners
 Poor immune function
HIV

7. Types of HPV
Based on their oncogenicity & strength associated with cervical cancer:
 High risk types: 16, 18, 31, 35, 45 and 58. (persistent HR
HPVoncogenic)
 Types 16 m/c in invasive carcinoma and CIN 2 & 3 (increased tendency
to persist)
 Low risk types: 6 and 11 (genital warts, sub-clinical HPV infections &
laryngeal papillomatosis)

8. Transmission
 Direct contact, usually sexual contact with genital skin, mucous membranes
or body fluids of partner with either warts or subclinical HPV.
 HR HPV cervical infection is generally limited to women who have
experienced penetrative sexual intercourse.
 Infects epithelial tissue through micro abrasions that exposes segments of
basement membrane.
 In most cases, infection is multifocal, involving more than one lower
reproductive tract site.

9. Transmission
 Formite transmission (non-genital warts)
 Less common: oral-to-genital & hand-to-genital transmission.
 Congenital: conjunctival, laryngeal, vulvar or perianal warts present at
birth or that appear within 1-3 yrs of birth is likely d/t perinatal
exposure to maternal HPV.

10. Pathogenesis of HPV Infection
Persistent infection with high risk HPV types affects the cell growth by the
following mechanisms:
 HPV integrates into host DNA  over expression of viral proteins E6 & E7
(high affinity for host cells).
 Viral proteins also activates cyclin A & E permitting further cell proliferation.
 Also mediate and degrade BAX (proapoptotic gene)  inhibits apoptosis.

11. immortalization
Unregulated cell cycle
p53 degradation
Activates E6AP
Binds p53
HPV E6
Cell cycle progression
p-Rb + E2F
Binds p53, p21 & Rb gene
HPV E7

13. Major risk factor : early age at coitus, multiple sexual partners, high-risk male sex partner.
HPV infection
Epithelial changes in basal cells of squamous epithelium
Low risk types (6,11)
Episomal infection
Condyloma acuminatum
Regression
High risk types (16,18,31,33,52,58)
Integration
CIN 1/L-SIL
Persistence of HPV infection
CIN 2,3/ HSIL
Invasive cervical cancer

14. Outcomes of
HPV infection
Latency
Subclinical infection
Intraepithelial neoplasia
Invasive carcinoma
Spontaneous
clearance
Condylomata
Persistence of infection
& E6,E7 oncogene
expression

15. Latent infection:
 Cells are infected but HPV remains quiescent.
 Viral genome is intact (not integrated to host cell).
 No detectable tissue defects.
Productive HPV infection:
 Completion of viral life cycle  increase in virus.
 Oncogenes are expressed in very low levels.
 Both in males & females, produces either genital warts (condyloma
acuminata) or subclinical infections.
 Subclinical infection maybe indirectly identified in cytology as LSIL.

16. Neoplastic HPV infection:
 In CIN3 & cancerous lesions, circular genome breaks open  integrates
linearly at random locations in host chromosome.
 Unrestricted transcription of E6 & E7 oncoproteins interfere with
functions of tumour suppressor genes  infected cell vulnerable to
malignant transformation by:
 Loss of cell cycle control
 Accumulation of nuclear mutations
 Degree of abnormal epithelial maturation used to grade lesion
histologically as mild, moderate or severe dysplasia or CIN.

17. Condyloma Acuminatum
 Also known as ano-genital warts is benign papillary lesion of sq.
Epithelium.
 Contact transmission
 Usually, they are multiple forming soft warty masses.
 Common sites: anus, perineum, vaginal wall & vulva.

18.  Caused by HPV 6 & 11
 Microscopically: tree like proliferation of stratified
squamous epithelium, marked acanthosis,
hyperkeratosis, parakeratosis, perinuclear
vacuolisation (koilocytosis)
 Tx: regress spontaneously.
 Podofilox 0.5% sol/gel
 Imiquimod 5% cream daily bedtime
 Siecatechin 15% ointment

19. Diagnosis
 Suspected by clinical appearance of the lesion & cytology, histology
& colposcopy
HPV testing is done:
 Cervical cancer screening in women > 30 years
 Triage or surveillance of abnormal cytology results
 Post treatment surveillance.

20.  Detection of HPV DNA:
 Polymerase chain reaction
 Digene HC2 HR HPV DNA Test- uses a mixture of RNA probes to detect 13
oncogenic HPV types
 Cervista HPV HR Test: digene + HPV 66
 Southern blot
 Hybrid capture
 If cervical cytology & HPV tests are negative  negative predictive value is very
high (99%)
 HPV typing is used
 As an adjunct test in evaluating abnormal cervical cytology.
 In evaluating atypical squamous cells of unknown significance(ASCUS)

21. HPV triage strategy
Can detect CIN II & III lesions effectively
Includes:
 Pap smear test  atypical smear after excluding infection
 HPV testing  positive for high risk HPV  Colposcopy  Biopsy
 negative  repeat smear after one year

22. Prevention
1. HPV vaccines: safe & well-tolerated
 Synthetic production of L1 capsid proteins of each HPV.
 Highly immunogenic
 Gardesil: quadrivalent vaccine (types 16, 18, 6 & 11)
 Cervarix: bivalent vaccine (types 16 & 18)
 Dose: 3 doses in 6 months
 Timing: ideally before commencement of sexual activity. (12-18 yrs)
 Effective for about 7½ yrs.

23. 2. Use of Condoms: prevent HPV transmission through body fluids &
across mucosal surface.
3. Behavioural interventions: sexual abstinence, delaying coitarche &
limiting the number of sexual partners.
4. Maintain local hygiene & to treat vaginal infections.
5. Male partner should also maintain penile hygiene as it may be
reservoir of high risk HPV.
6. Quit smoking