A 27 year old woman presents with genital warts. What type of virus is likely causing her condition and why might she be at high risk for cervical cancer?
She most likely has HPV. It is an icosahedral non-enveloped dsDNA virus. She is at risk for cancer because viral genes E6 and E7 inactivation tumor suppressors p53 and Rb respectively, promoting S phase entry and DNA replication.
A 27 year old man presents with vesicular lesions, a fever and nuchal rigidity. He has had eruptions of the vesicular lesions a couple times in the past few years. What type of virus is likely causing his condition and how could you treat him?
HSV-2 is an enveloped dsDNA virus. It encodes DNA enzymes for limited replication in neurons that allows for the latent neuronal phase. It encodes DNA enzymes with robust replication in epithelial cells that causes the lytic epithelial phase. Note that HSV-2 can also cause CNS infection.
Why are viruses common causes of human cancer?
Some act as direct carcinogens w/viral oncogenes integrated into cancer cell DNA, some induce immunosuppression, chronic inflammation or activate ROS and/or NOS.
Common cancer linked to HPV in men
HPV serotypes that result in genital tract condyloma acuminatum
6 and 11
HPV serotypes that result in genital malignancies
16, 18, 31
HPV serotypes that result in respiratory papillomas in children
HPV serotypes that result in plantar warts
1, 2, 4
Why can HPV be spread by skin to skin contact and not just sexual contact?
It is environmentally stable and released from epithelial cell lysis. Since it is non-enveloped it remains infectious despite drying out, digestion and detergent exposure.
When are the early HPV genes expressed and when are the late HPV genes expressed in HPV replication?
HPV infects epithelial cells -> Plasmid expresses early genes (E1, E2, E6, E7) in basal cells -> Early genes stimulate proliferation of basal cells -> Late genes (L1, L2, E4) are expressed -> Lysis of differentiated keratinocytes in upper epithelium
What are the early HPV and late HPV genes?
E1 (replication initiation), E2 (transcription), E4 (disruption of keratin), E5 (growth factors stimulated), L1 & L2 (capsid protein synthesis), E6 & E7 (push cells into S phase)
What differentiates cervical intraepithelial neoplasia from invasive carcinoma?
CIN is confined to the epithelial basement membrane and virus is still being produced. Carcinoma breaches the basement membrane, no virus is being produced and HPV is integrated into the epithelial DNA.
What cells would you find on Pap smear of this cervix?
Note the micropapillary and microconvoluted structure. Pap smear would show vacuolized epithelial cells indicating an HPV-infected cervix.
How does HPV's E7 protein cause cancer? E6?
E7 binds and inactivates Rb. This frees E2F to drive DNA transcription. E6 destroys p53 that allows for aberrant DNA replication with DNA that has damage in it.
Aside from removing tumor suppressor genes, how is cancer growth promoted by viral infection?
Viral integration and retroviral oncogenes activate transcriptional activators and protooncogens respectively.
HPV most often associated with cervical carcinoma
HPV-16 > 50% of the time
What is the initiating event of viral infection that starts the path of carcinoma development?
Integration of the viral genome, disruption of E1/E2 and maintenance of E6/E7 genes.
Koch's postulates for viral oncogenesis
1) Virus associated w/specific malignancy 2) Virus present in each malignancy 3) Virus transforms target cells into cancer cells 4) High incidence of cancer in areas endemic with virus
Tetravalent HPV vaccine (Gardasil) serotypes
16, 18, 6 and 11.
Bivalent HPV vaccine (Cervarix) serotypes
16 and 11
A woman presents with a large and flat papule on her cervix. It turned whit with application of 4% acetic acid. Her pap smear showed koilocytic cells. What is the diagnosis?
How do HSV-2 particles exit the cell they are finished replicating in?
They bud through nuclear membranes and into membranes of exocytic vesicles.
What is the most common manifestation of HSV-2 infection?
Genital herpes is very common and usually resolves. Neonatal herpes is very rare and there is impaired fetal development.
When is neonatal HSV-2 infection a high risk?
Primary (non reactivation) HSV-2 infection prior to child birth poses the highest risk.
What therapies are available for treatment of herpes?
Acyclovir and ganciclovir (herpes thymidine kinase): incorporate into viral DNA where viral thymidine kinase is present and terminates DNA chains. Herpes DNA polymerase (PAA). Forscarnet (PFA): binds to the pyrophosphate-binding sites of RNA or DNA polymerases, it can also be used in CMV and AIDS.
What do acyclovir, famcyclovir, gangcyclovir and valacyclovir all look like?
What virus does not have a viral thymidine kinase but can still be inhibited by ganciclovir?
CMV. It has a protein kinase homologue.
Anti-viral drug that does not need to be activated by cellular or viral kinases and also has renal side effects.
What proteins are turned off by E6 and E7?
E1 and E2