Background Information:

Human Papilloma Virus is responsible for causing epithelial lesions (e.g., warts) and some epithelial cancers.  There are over 100 subtypes of HPV, some of which can cause 3 different types of lesions: non-genital (cutaneous) lesions, mucosal or genital lesions, and various epithelial cancers (e.g., cervical cancer, and some laryngeal, oral, lung, penile, and anogenital cancers).  Usually, HPV infection alone doesn’t cause cancer, but with multiple factors combined (e.g., smoking, UV light exposure, immunosuppression, pregnancy and/or repeated HPV infections).  HPV infects the skin and enters the basal stem cells of the epidermis.  As HPV can be sexually transmitted, multiple sexual partners increasing one’s risk for the HPV genital infections.  HPV infections on other parts of the body (e.g., feet) can occur through contact with the virus in rec centre change room facilities.  In the USA, it is estimated that 45.2% of males and 39.9% of females (aged 18-59) are infected with genital HPV.  In total, more than 42 million Americans are currently infected with HPV and 13 million Americans become infected each year.  Stats in Canada are likely similar.

Some subtypes of HPV are oncoviruses and lead to DNA mutations in basal epidermal stem cells that transform the cells into immortal cancerous cells.  Cervical Pap smears are available for females and anal Pap smears are available for males.  Although many cases of HPV infection are asymptomatic, signs & symptoms of HPV anogenital infections include: bleeding, pelvic/genital pain, and/or palpable lesions.  Pap smears can reveal dysplasia and concurrent HPV testing can indicate the need for follow-up tests, which can include colposcopy and targeted biopsies and DNA testing.  Treatments of cutaneous & anogenital warts can involve surgical removal, cryotherapy, and laser removal.  Further treatment (e.g., chemotherapy and/or radiation) may be required if transformation to malignant cancer has occurred.  Prevention of anogenital HPV infections involves vaccination prior to HPV infections, often given at 11-12 yrs old.  Other means of prevention include use of barriers (e.g., condoms) during sexual intercourse, though this is not 100% preventative as it doesn’t eliminate all skin-skin contact.  Treatment of sore arms and mild fever that sometimes occurs during vaccination involves the use of acetaminophen and/or ibuprofen.  ASA (aspirin) is typically not given, especially to those under the age of 18 due to the risk of developing Reye syndrome.

Word Bank: Possible Lesson 1&2 Terms:

pathogen, exogenous, endogenous, morbidity, mortality, epidemic, endemic, pandemic, communicable, latent, subclinical, acute, chronic, lesion, neglected tropical disease, atrophy, hypertrophy, hyperplasia, metaplasia, dysplasia, anaplasia, neoplasia, immature, dedifferentiate, dysfunctional, non-functional, proliferation/mitosis, true/false negative test results, true/false positive test results, sensitive test, specific test, redness, warmth, swelling, exudate, pain, histamine, bradykinin, prostaglandin, capillary permeability, vasodilation, chemokines, lymphokine, diapedesis/emigration/transmigration, chemotaxis, inflammatory cytokines, C reactive protein, (erythrocyte sedimentation rate, ESR), neutrophils, basophils, mast cells, eosinophils, macrophages, dendritic cells, Helper T cells, Cytotoxic T cells, Memory B cells, Plasma Cells, Antibodies, Opsonization, Interferons, Anti-Viral Proteins (AVPs), free radicals, Reactive Oxidative Species, (ROS), phagocytosis, pyrexia, Memory Helper T cells, Memory Cytotoxic T cells, Suppressor T cells, NK lymphocytes, Primary & Secondary Response.

Title:  Human Papilloma Virus Infections – Information Sheet                        Team-Lead Name: ____________________

Etiology:

Human Papillomavirus infection, HPV is a non-enveloped, double-stranded, circular DNA virus

Risk Factors:

sexual activity, number of sexual partners (as increases likelihood of contact with oncovirus strains of HPV), transmitted through skin-to-skin contact

Prevalence & Incidence:

the most common STD worldwide, ~50% of sexually active adults

Pathogenesis

(List the steps of cellular & morphological changes that occur if infected with HPV oncovirus):

1. HPV infects basal keratinocytes (epithelial cells) of the epidermis of skin or mucosal surface.
2. HPV can produce epithelial benign/malignant tumors of the skin and mucous membranes.
3. Some strains (subtypes) of HPV cause DNA mutation when they integrate their genome into the host DNA. Co-factors such as tobacco use, UV radiation (and other carcinogens), pregnancy, folate deficiency, immune suppression, female oral contraceptive use, pregnancy increase the risk of cancer-causing DNA mutations occurring.
4. Specifically, once inside basal epithelial cells, cancer-causing HPV strains/subtypes produce 2 viral proteins (oncoproteins that inactivate stability proteins (p53 and pRb) that can lead to DNA errors during DNA duplication during mitosis. Other carcinogens (e.g., tobacco) can lead to more DNA mutations.  These DNA mutations can give rise to hypertrophic lesions (e.g., warts) and possibly dysplasia and anaplasia (unregulated and continuous mitosis, immortality = cell becomes cancerous).
5. Summary: HPV infection can give rise to genital and non-genital warts, lesions, and cancers (e.g., cervical cancer, anal cancer).  Non-cancerous genital warts can regress spontaneously or with treatment (see below). Cancers require treatment (see below)

Steps of Inflammatory Response:   

1. Cellular damage (the release of cellular contents) as well as presence of foreign material (e.g., viral/bacterial/fungal) triggers the release of vasoactive cytokines (e.g., histamine, leukotrienes, prostaglandins, bradykinins) from Mast Cells and Basophils. These vasoactive cytokines:
2. Bind to blood vessel walls inducing vasodilation and increased capillary permeability. The resulting increase in blood flow causes Redness and Warmth. The exudate leaking from the capillaries causes Swelling.  Pain is caused by nociceptors (pain-relaying sensory neurons) being triggered by: a) the pressure from the leaking exudate; b) chemicals released during cellular damage; c) prostaglandins and d) leaked blood.
3. Mast cells and Basophils also release cytokines and chemokines that attract WBCs to the area to assist with eliminating any infection and removing cellular debris. Platelets are activated to wall off the area of damage. WBCs and surrounding epithelial and connective tissue cells release growth factors to stimulate mitosis, regeneration, and replacement of dead cells.  Cells that can not be replaced through regeneration lead to more collagen being laid down which contributes to scarring (fibrosis).

Differences in mechanism between aspirin, ibuprofen, acetaminophen, and corticosteroids:

1. Acetylsalicylic acid (ASA): eg. Aspirin
   Blocks COX-1/2 → ↓ production of PGs reducing inflammation, pain, & fever;
   Not to be used during viral infection → Reye’s syndrome (liver & brain damage)
   Can be an allergen; Can ↓ gastric mucus → can cause stomach irritation & ulcers
   Can interfere with blood clotting (reduces platelet adhesion)
2. Acetaminophen (e.g. Tylenol)
   Blocks COX-2 →↓production of PG E2 → ↓fever & pain , but not inflammation
3. Non-steroidal anti-inflammatory drugs (NSAIDs) e.g. Ibuprofen, Advil, Motrin – also works by blocking COX-1/2 → ↓ production of PGs
   Decrease fever, pain & inflammation; with less negative side-effects of aspirin
4. Glucocorticoids (steroidal anti-inflammatory drugs) e.g. Corticosteroids
   Decreases: capillary permeability (limits emigration/chemotaxis), # of WBCs, # mast cells, release of histamine, prostaglandins & leukotrienes
   Negative side-effects: lymphoid tissue atrophy (decreased # WBCs leading to risk of infection & reduced immune response); catabolism; thinning skin (peptic ulcers), delayed healing, delayed growth, high bp & edema (Na and H2O retention).
5. Catabolism:  protein → amino acid → glucose (gluconeogenesis)
6. Diagnostic Tools:  Sensitive test = Pap Test (cytologic testing), DNA testing, clinical analysis of lesions and warts (exhibiting hyperkeratosis and hyperplasia); if Pap Test is positive = Specific Test = colposcopy

Treatment:

1. For non-dysplastic and non-cancers: Cryosurgery/electrosurgery/scalpel excision/laser ablation of warts, immune response modifiers for anogenital warts, cytotoxic agents for nongenital warts
2. For dysplasia
3. For cancers: surgery/chemotherapy/radiation depending on stage/grade (spread and cellular characteristics) of cancer

Potential Complications:

non-genital and genital warts, cervical dysplasia and/or cervical cancer, vaginal cancer, penile cancer, throat cancer, anal cancer

Prevention:

condoms, HPV vaccine (prior to sexual activity)

Vaccine Mechanism (mode of action)

List Cellular Steps of WBC Response:

1. Injection of 14 HPV viral proteins from oncovirus strains to initiate Primary Response of the Specific Immune system (activation of B and T cells) as follows:
2. Phagocytosis of viral proteins by phagocytes such as macrophages, dendritic cells, and B lymphocytes (B cells) which will become Antigen Presenting Cells (APCs).
3. Activation of Helper T lymphocytes (i.e. T_H cells, CD4 cells) and Cytotoxic T lymphocytes (i.e., Tc cells, Killer T cells, CD8 cells),  through APC display of viral antigens on Class II MHCs and APC release of lymphokines (e.g., monokines and interleukins).
4. Helper and Cytotoxic T lymphocytes with T cell receptors (TCRs) that match/bind to the viral antigen being presented will proliferate producing daughter T_H cells, daughter Memory T_H cells, daughter T_C cells, daughter T_C  Memory cells, daughter T_R Regulatory cells.
5. T_H cells are instrumental in activating T_C cells and do so by binding viral antigen to TCR and releasing lymphokines.
6. Active T_C cells go on a search and destroy (seek and destroy mission) mission to destroy HPV viral antigens. Memory T cells allow for prolonged memory and faster response times during Secondary Response.
7. Activation of B lymphocytes begin with viral antigen binding to their IgD receptors and intake/phagocytosis of viral proteins – to become sensitized. Then, B cells display viral proteins on Class II MHCs and bind to Helper T cells that have also been activated (by their TCR binding to viral proteins).
8. Once activated B cells proliferate and their daughter plasma cells produce antibodies against HPV.  Their other daughter cells are Memory B cells.
9. Antibodies travel the bloodstream (and other regions) to bind viral antigen, targeting it for destruction.
10. Regulatory T cells will de-activate the B and T cell response once the viral antigen or infection has been eliminated.
11. The build up of Memory B, Memory T_H cells, and Memory T_C cells allows for a very rapid (secondary) response the next time the person is exposed to HPV, meaning that it can eliminate the virus before it has a chance to enter cells and cause cancer.