Papillomaviruses (HPV)- discovery, epidemiology, detection

Question 1

Is HPV a DNA or RNA virus?

Answer 1

HPV is a DNA virus

Question 2

In classical times, genital warts were linked with promiscuity. In the 1800s, Rigoni-Stern noticed cervical cancer in which groups of people?

Answer 2

Married women and prostitutes

Question 3

In the 1900s, what was thought to be the cause of cervical cancer?

Answer 3

Firstly, transmissionable microbes. Then the use of molecular cloning allowed for the structure of PV to be studied and along with southern blotting elucidated that HPV-18 caused cervical cancer (instead of the previously thought Herpes virus)

Question 4

Who is Harald Zur Hausen, Francoise Barre-Sinoussi and Luc Montagnier?

Answer 4

Hausen- Discovered HPV causing cervical cancer

Barre-Sinoussi + Montagnier- contributed to discovery of HIV

Question 5

Which sort of species is HPV commonly found in?

Answer 5

Vertebrate species- dogs, mice, cats, cows, not just humans!

Question 6

How big are HPV particles and their genomes? Are the warts that it causes benign or malignant?

Answer 6

Around 55nm diameter (small)+ 8kb double-stranded circular DNA genome. The warts are usually benign but can progress into malignancy

Question 7

What species has been helpful in learning about HPV?

Answer 7

Transgenic mice. Most species are not very similar to humans so the lifecycle of HPV has been hard to study

Question 8

In regards to the papillomavirus structure, what is the capsid like (what two main proteins form it) and does it have an envelope?

Answer 8

Icosahedral capsid (polyhedron with 20 faces). The two proteins are called L1 (major) and L2 (minor). The virus has a non-enveloped protein shell

Question 9

Before the papillomavirus was classified in the Papillomaviridae family, which family was it under? What is the classification based on?

Answer 9

Papovavidae. The L1 major capsid protein sequence was used for the classification of HP

Question 10

Why is antibody and serology not very useful in distinguishing between types of papillomaviruses?

Answer 10

Most of them are very similar

Question 11

What are alpha PVs and what are beta PVs?

Answer 11

Alpha PVs are muscosal PVs; associated with ano-genital cancers e.g HPV 16 and 18 (cervical cancer related)

Beta PVs are cutaneous PVs; associated with non-melanoma skin cancers

(side note- alpha, beta and gamma= human types)

Question 12

There are early and late regions of the genome. Knowing this, what prefix is given to those genes which are expressed early on and to those later?

Answer 12

‘E’ e.g E7 and ‘L’ e.g L2

Question 13

What is the region ‘URR?’

Answer 13

The Upstream Regulatory Region- the region where DNA polymerases attach (called ‘ori’ for origin of replication) + binding site for post-RNA polymerase II that is involved in transcribing the open reading frames

Question 14

Apart from using the host DNA polymerase, what does HPV have which helps in DNA replication?

Answer 14

E1 has a helicase activity which unwinds the DNA which binds to ‘ori’ and this is facilitated by E2. E2 is a transcription factor and represses E6 and E7 (oncoproteins)

Question 15

What is E6, E7, E5 and E4 involved with? (brief)

Answer 15

E6 and E7 are oncoproteins and disrupt the cell growth cycle. E5 is involved with membrane protein signalling and is also considered an oncoprotein. E4 is involved in assembly and release of virus from epithelium

Question 16

What is the difference structurally/genetically between beta and alpha PVs?

Answer 16

Beta PVs don’t seem to encode E5 except from Bovine PV in which E5 is a major viral oncoprotein rather than E6 and E7. Also, E6 and E7 do not interact with p53 and Rb proteins respectively in the same way as in alpha PVs

Question 17

Specifically in human papillomavirus, there are more than 100 genotypes/ types (defined by L1 sequence relationships). There are cutaneous genotypes such as HPV-1 or 2, that cause benign skin warts, and genital genotypes lesions. Within genital genotypes, how may the viruses be classified?

Answer 17

Low-risk e.g HPV-6 or 11 that cause benign lesions or condylomata

High-risk e.g HPV 16 or 18 that cause intra-epithelial lesions and ano-genital cancers

Question 18

What is different about the bandicoot PV?

Answer 18

Seems to have traits from polyomavirus and papillomavirus suggesting an ancient recombinant even

Question 19

How is HPV most likely transmitted?

Answer 19

Genital types= sexual contact
Breaks in epithelium
Abrasion and shedding from the sloughed squames of the keratinised epithelium

Side note- remember that cervical cancer can take years to develop so isn’t always apparent when HPV is contracted

Question 20

Type of PV= Common wart

What HPVs cause this?
How is it transmitted?
What is its clinical significance?

Answer 20

Common wart

Cause: HPV-2, 4 and 7
Transmitted: through breaks in dead cell layer- direct contact
Clinical significance: Common and superficial

Question 21

Type of PV= Flat (planar) wart

What HPVs cause this?
How is it transmitted?
Which organ is affected?
What is its clinical significance?

Answer 21

Flat (planar) wart

Cause: HPV-3, 10
Transmitted: break in dead cell layer-direct contact
Organ affected: skin-usually face and knees
Clinical significance: numerous, primarily in children

Question 22

Type of PV= Plantar/ Palmer wart

What HPVs cause this?
How is it transmitted?
Which organ is affected?
What is its clinical significance?

Answer 22

Plantar/ Palmer wart

Cause: HPV-1, 2, 4
Transmitted: break in dead cell layer-direct contact
Organ affected: skin- usually heel and sole of foot
Clinical significance: deeper, difficult to remove

Question 23

Type of PV= Genital wart

What HPVs cause this?
How is it transmitted?
Which organ is affected?
What is its clinical significance?

Answer 23

Genital wart

Cause: HPV-6, 11, 16, 18, 31, 33
Transmitted: break in dead cell layer-sexual contact
Organ affected: skin- genital area
Clinical significance: 16, 18 (31, 33) associated with cervical carcinoma

Question 24

Type of PV= Laryngeal wart

What HPVs cause this?
How is it transmitted?
Which organ is affected?
What is its clinical significance?

Answer 24

Laryngeal wart

Cause: HPV-6, 11
Transmitted: During birth
Organ affected: Exposed epidermal cells of larynx
Clinical significance: rapid growth and may cause loss of speech (recurrent respiratory papillomavirus)

Question 25

Type of PV= Epidermodysplasia Veruciformis (EV)

What HPVs cause this?
How is it transmitted?
What is its clinical significance?

Answer 25

Epidermodysplasia Veruciformis (EV)

Cause: HPV-5, 8
Transmitted: Direct contact; specific host genotype
Clinical significance: rare but readily undergo malignant conversion

Question 26

There are co-factors that contribute to benign and malignant cancers along with PVs. What are these?

Answer 26

In bovine PV, there are chemicals in their food (bracken) which are associated with digestive and urothelial cancers
Sunlight in non-melanoma HPV-associated skin cancers (e.g. EV)
Hormones – estrogens, endogenous or exogenous (contraception) in cervical cancer
Smoking
Host genotype - HLA association of cervical cancer; EV (see zur Hausen review)

Question 27

What is used for the detection and diagnosis of HPV?

Answer 27

Cytology – Papanicolaou (Pap) smear detects abnormal cells (koilocytes) indicative of HPV infection
Serology – not generally useful (>100 human genotypes) – detection at the DNA sequence level preferred from smears or biopsies
PCR primers designed in L1 ORF
Commercial assays (Digene)
In situ hybridisation
Immunocytochemistry (for productive infection with antibody against capsid proteins)

Question 28

What is the main HPV test?

Answer 28

Digene test which is a hybridization test - The digene HC2 HPV DNA Test uses an RNA probe cocktail that detects 13 high-riskHPV types (16/18/31/33/35/39/45/51/52/56/58/59/6) and 5 low-risk types (6/11/42/43/44)