Papilloma viruses: from tip to tail Tim Palmer

Taxonomic level CriteriaNumber Genera Less than 60% nucleotide (nt) identity in entire L1 ORF 18 genera (alpha to sigma) 2 additional new genera, yet unnamed (containing TtPV2 and RaPV1 respectively) SpeciesBetween 60% and 70% nt identity in L1 From 1 species (in most genera) up to 15 species (in genus alpha) GenotypesBetween 71 and 89 % nt identity in L1 Currently 120 papillomavirus genotypes completely genomically characterized and available in Genbank (98 human: HPV; 32 non-human) SubtypesBetween 90 and 98 % identity in L1 Very rare VariantsMore than 98 % identity in L1

Lineage C more persistent than A or B A and B more commonly associated with CIN3 Lineage B - higher association with CIN3 (2.7 OR) HPV 31

Non-human papilloma viruses Bovine (6 types) Equine Canine Feline Rabbit (2 types) Mouse Hamster Deer Reindeer European elk Sheep Porpoise Monkey (Rhesus and chimpanzees) Parrots Chaffinch Tortoise Manatees

Squamous epithelia – keratinising and non-keratinising o Cutaneous o Genital o Aero-digestive tract Papillomas Fibropapillomas ‘Sarcoids’ Malignant transformation

Illustration from Tableau Encylopedique and Methodique 1789 Cottontail rabbit with cutaneous papillomatosis – Shope papilloma virus (Museum Nat Hist, Kansas)

Evolved at the same time as reptiles DNA virus Protein coat (capsid) Early and late genes E6 and E7 necessary for transformation (immortalisation) L1 and L2 form capsule L1 most conserved part of genome L1 capsid protein used for vaccines Papilloma viruses

HPV genome

Human disease Cutaneous warts o Ano-genital warts o Verruca vulgaris, plana, plantaris etc o Epidermodysplasia verruciformis Mucosal warts o Cervical o Oral o Anal o Laryngeal

HPV immunisation in Scotland September 2008 Cervarix ® immunisation starts at age yr Catch-up cohorts up to age 18 (dob 1990) September 2010 First immunised women start screening September 2013 Three full years of data available from four year cohorts of catch-up programme September 2015 First ‘HPV-naïve’ women start screening

Data available for analysis Year of birth Total in year of birth Number with smearsTotal with smears Full1 or 2 doses None Total

Immunised women more likely to be screened - p < for all cohorts

Any immunisation associated with less HG dykaryosis – p <0.0001

Immunisation associated with less low grade dyskaryosis – p < Significant difference between cohorts in percent low grade dyskaryosis

Full immunisation only associated with less borderline changes – p <0.0001

Full immunisation only associated with less HG CIN in all cohorts – p< Partial immunisation associated with less HG CIN in 1990 only – p<0.0001

Full immunisation associated with less LG CIN in all cohorts – p< Partial immunisation associated with less LG CIN in only – p<0.0001

Oro-pharyngeal cancer Explosion in last 15 years Tonsil, base of tongue, basaloid HPV 16 almost exclusively ? Pre-invasive phase >= 50% HPV driven non-smoker, non drinker, male > female, young > old, I >V Better prognosis, stage for stage

Anal squamous carcinoma Used to be uncommon HPV driven in many cases HIV +ve: almost all are HPV+ Anal canal may be reservoir for HPV in male and female Pre-invasive disease Screening