Human Papillomavirus

Question 1

HPV

Answer 1

circular ds genome but only one strand is transcribed; encodes for 7 early genes (E1-7) and 2 late genes (L1-2); E6 and 7 are transcribed first; E2 is transcriptional regulators which represses E6-7; E6 binds to p53 mediated by cell protein (E6AP) which promotes degradation of p53 E6 and cooperates with E7 to immortalize human fibroblasts and NIH 3T3 cells; removing p53 allows virus to proliferate

Question 2

E7

Answer 2

Related to adenovirus E1A and SV40 T antigen; binding to pRB causes release of E3F allowing progression of cells through G1 to S; can bind to p107 and p130 (RB related proteins) as well as cdck2 and cyclin A; expression in NIH3T3 cells lead to constitutive expression of cyclin E and cyclin A in the absence of growth factors; activation of both cyclin E and A co segregates with the ability of E7 to transform cells; also complexes with AP1 transcription factors

Question 3

Replication

Answer 3

Virus infects basement epithelium of skin; the basal cell in the squamous epithelium is the only cell capable of dividing and these epithelial cells are non permissive for virus replication; HPV DNA remains in nucleus of infected cell as episome where it replicates when cell DNA replicates; HPV expresses E5-7 that induce cells to replicate more frequently; as cells divide they begin to differentiate which stimulates viral replication; once differentiation occurs late viral genes are expressed when cells produce keratin and other terminally differentiated gene products; HPV genome remains episomal in benign warts but in malignant cells HPV genome appears to be randomly integrated into host DNA; integration causes disruption of E3 which results in up regulation of E6 and E7 and stability of mRNAs

Question 4

Papillomavirus

Answer 4

• known to cause warts or a tumor system of oncogenic potential
• E6-7 promote growth of these cells
• Once keratin is produced the virus can replicate
• 60 human types associated with diseases
• types 6-10-11 associated with warts
• types 18-18-31-32 associated with cervical carcinoma and anogenital cancers; cervical cancer is the 2nd most malignant tumor of women with 500,000 new cases per year (6% of global incidence); HPV may be a causative agent or at least a risk factor for > 10% of all cancers(has a higher probability of causing cancer than smoking/chewing tobacco)

Question 5

HPV 1

Answer 5

Foot warts

Question 6

HPV 45 and 18 and 31 and 16

Answer 6

cervical cancer

Question 7

HPV 6 and 11

Answer 7

genital warts

Question 8

HPV 2

Answer 8

hand warts

Question 9

Papillomavirus

Answer 9

Epi evidence supports feature that HPV is a factor in CC
Pros: greater than 955 of the CC tumors contains HPV genome and 90% are types 16-18-31; retinoblastoma gene is wild type in tumors that contain HPV and mutant in tumors lacking HPV; data supports a horizontal mode of transmission
Cons:

Question 10

Diagnosis

Answer 10

Pap smear: 61-66% sensitivity and 82-91% specificity

Hybrid capture 2 high risk HPV DNA test: DNA virus + RNA probes–> conjugated antibodies on plate –> chemiluminescence

Question 11

Treatment

Answer 11

Warts: salicylic acid (compound W), cryosurgery, electrosurgery, laser
Genital warts: imiquimod cream (immune modulator TLR 7), podophyllin and podofilox, homeopathic remedies..20-50% of warts return
Vaccine: gardasil (merck) for types 16-18-6-11 (HPV 16 and 18 cause 70% of CC and 6 and 11 cause 90% of genital warts); major capsized protein L1 that spontaneously self assembles into virus like particles; three injections over 6 months; 2006 advisory committee of immunization gave approval for immunization of children 9 y.o; routine vaccination recommended for females 11/12; unknown for females age 19-26; males as young as 9 and between 13-26; not recommended for females over 26; problems are cost, insurance cost and physician surcharge, promote sexual behavior