Lecture 9.0 Oncogenic Viruses Flashcards
List the factors that trigger oncogenesis
- Environmental carcinogens:
(Nicotine, radiations, chemicals, hormones, diet, etc)
– Human genetic predispositions
– Immunodeficiency
– Loss of tumor immunity
(mutation acquired over a period of time)
– Infectious pathogens
(i.e., Viruses)
Name 3 classes of regulatory genes contributing to oncogenesis
- Tumor-suppressor genes / anti-oncogenes
*e.g: p53 (Nuclear protein); pRb (Retinoblastoma protein)
– Proto-oncogenes
* e.g: c-myc (promoting cell growth & differentiation)
– Apoptosis regulating genes:
Induced cell death (mutation, DNA damage, ect)
Discuss the mechanism of oncogenic viruses
- Inactivate tumor-suppressor genes
*E.g: HPV proteins → promote the degradation of p53 & pRb
→ cervical cancer
– Activates cell proto-oncogenes
*E.g: Epstein Barr virus proteins → immortalization of B-
lymphocytes
– Inhibit apoptosis of damaged cells by inducing bcl-2
– DNA mutations due viral integration & error-prone viral RNA Polymerase
– Immune modulation → chronic activation of inflammation
List the DNA tumour viruses
- Human papillomavirus
(HPV) - Hepatitis B virus (HBV)
- Herpes viruses
*Epstein-Barr virus (EBV)
*Kaposi sarcoma virus - Polyomaviruses
*Merkel cell polyomavirus
*JC virus
List the RNA tumour virus
- Hepatitis C virus (HCV)
- Human retroviruses
-Human T-cell leukemia
virus I (HTLV-I)
Discuss features of HPV
Have over 200 types:
– High risk types: associated with malignancy (16 & 18)
– Low risk types: warts (6 and 11)
– Predominant HPV types in SA: 16, 18 followed by 35 & 45
HPV transmission routes
- Sexual transmission
- In utero or perinatal
- Autoinoculation or
indirectly i.e fomites
Discuss the oncogenesis of HPV
- Integration of HPV DNA into
the host chromosomes - Viral proteins interfere with the
control of cell cycle
– E6 binds to p53
– E7 binds to pRb - Activation of c-myc by nearby
integration of HPVDNA - Cause a range of mucosa & cutaneous lesions
– Majority clear the infection within 1-2 years
– ~5–10% of cases → persistent
HPV screening tests, and appropriate samples
HPV screening tests
– Molecular assays
* DNA PCR
– Reflex testing
* Cytology
Sample
* Liquid-based cytology
* Self sampling (vaginal swab)
What are the risk factors for persistent infection & cervical cancer?
Multiple sexual partners
Immunosuppressive states
Early age at first delivery; High parity
Long-term oral contraceptive use
STIs i.e., Bacterial vaginosis
Name the 2 HPV screening test
- Molecular assays
DNA PCR - Reflex testing
Cytology
General measures and clinical prevention methods ze HPV
- Behavior change:
–Limiting high risk exposure - VACCINATION:
–Cervarix (serotypes 16 and 18 )
o Virus-like particle vaccine
o Two doses, administered 6 months apart to girls aged 9-12 or up to 15 yrs - Private sector:
- Gardasil 4 (serotypes 6,11, 16 & 18) or 9
- HPV screening (SA Guidelines)
– All women should initiate HPV screening from the earliest age of 25 years or at the time of a positive HIV diagnosis
Replicates via an RNA intermediate
– Partially dsDNA. Therefore, uses reverse transcriptase
HBV
Explain the progression of HBV
Acute infection with HBV»Chronic infection»Liver cirrhosis»Hepatocellular carinoma or just liver failure will result»eventually you die from either outcomes
What disposes an individual to HBV Oncogenesis?
- Chronic or persistent infection with HBV
-Early childhood HBV infection can result to chronic HBV infection (in 90% of
cases) - Adults majority clear the infection; only 1-8% have chronic HBV
Interpretation of HBV surface markers:
What can you learn from the presence of HBV surface antigen in patient serum?
The presence of HBsAg indicates that the person is infectious
– HBsAg is detected in high levels in serum during acute or chronic hepatitis B virus infection
What;s the appropriate treatment for hepatitis b v?
ARVs: for HIV / HBV co-infected pts
– HBV mono-infection; refer pts to hepatitis clinic
Discuss the oncogenesis of HBV
– Viral integration to host DNA or viral proteins
- Random mutagenesis (insertional mutations)
- Transactivation of cellular oncogens
- Inactivation of tumour suppressor genes
– HBV chronic infection leading to liver damage
How is HBV transmitted?
Sexual; Blood/ Parenteral; Perinatal; Horizontal
How to diagnose HBV?
Serology
* HBV surface antigen (HBsAg) – marker of HBV infections
- Chronic HBV: sAg (+) for >6 months
– HBV viral load = monitoring
Interpretation of HBV surface markers:
What can you learn from the presence of HBV surface antibodies in patient serum?
- The presence indicates recovery and immunity from hepatitis B virus infection.
– Anti-HBs also develops in a person who has been successfully
vaccinated against hepatitis B (>10 IU/ml
An oncogenic virus High in Egypt;
– Intermediate seen in
Ethiopia, Saudi Arabia,
Europe & Asia;
– Low incidence in SA
Hepatitis C
3 ways to prevent for HBV infection
- Vaccination:
– Infant immunization (EPI)
oStandard practice – HBV vaccination at birth
oCurrently – @ 6, 10 & 14 weeks then booster @ 18 months and @ 4-6 years
– Adult
- Hepatitis B Immunoglobulin:
– Adult Post Exposure prophylaxis
-Individual who lack of HBV immunity
– Babies Post Exposure prophylaxis
-For babies to HBV infected mothers
-HB Ig + HB vaccine → administered within 12hrs of birth - Prevention of high-risk behaviors:
– Unprotected sexual intercourse
– Intravenous drug users
– Screening of blood
Interpretation of HBV surface markers:
What can you learn from the presence of Hepatitis B core antigen IgM (anti-HBc IgM) in patient serum?
Its presence indicates acute/recent infection (<6 months)
Interpretation of HBV surface markers:
What can you learn from the presence of Hepatitis B core antigen (anti-HBcA)in patient serum?
The presence indicates previous or ongoing infection (exposure) with hepatitis B virus in an undefined time frame and persists for life
How to manage HCV?
Management
– No vaccine
– Antiviral therapy → viral clearance in 90% of cases
Techniques to diagnise HCV in the lab
Lab Diagnosis
– Screening test: HCV Ab
– Confirmatory test: HCV RNA PCR
Discuss oncogenesis of HCV
– Persistent HCV infection is a pre-requisite for tumor formation
Common cause of infectious mononucleosis
Epstein Barr
*Infects and cause immortalization of B-lymphocytes into
lymphoblastoid cells
–Also infect T-lymphocytes, epithelial cells & smooth
muscle cells
How is Epstein Barr Transmitted?
- Infected oropharyngeal secretions
- Blood
- Transplant solid donor organ
Tumour of the jawline resulting from infection with Epstein Barr
Bukirt lymphoma
*Lymphoma of childhood
*Occurs in children from tropical Africa & Papau New Guinea
Discuss the oncogenesis of Burkit lymphoma
Oncogenesis:
- Result from the translocation between the c-myc on
Chromosome 8 & 14 or
Chromosome 2 & 22
o Associated with depressed CMI –due to burden of malaria
-Malaria – act as a co-factor
Name other tumors associated with Epstein Bar virus
- Post transplant lymphoproliferative disease (PTLD)
- Nasopharyngeal ca
– Cancer of the epithelial lining of the oro-nasal mucosa
– Common in South East Asia – suggested co-factors
o Genetic susceptibility
o Chemical carcinogens in their diet - Hodgkin’s & Non- Hodgkin’s lymphoma
- Primary CNS lymphoma
- X-lymphoproliferative disease (Duncan syndrome)
- Smooth muscle tumors 28
Discuss the oncogenesis of Epstein Barr virus
- Viral oncogenes: LMP, EBN-
Ag & EBE-RNA causes
widespread immortalization
of B-cells - EBV linked cancers are
associated with absence or
depressed cell mediated
immune response
How tto diagnose Epsein bar?
EBV PCR / viral load → blood, plasma or CSF
– Excisional tumor biopsy or core needle biopsy
Human herpes virus 8 neoplasia; 1st identified in 1994, in AIDS patients; prevalence higher in Sub-Saharan Africa
Kaposi sarcoma
Treatment for Epstein Bar
- No vaccine against EBV
- Reducing immunosuppressive – PTLD
- ARVs may be of benefit to HIV patients
- Anecdotal support regarding the use of;
oHerpes antivirals – acyclovir or ganciclovir
oImmunoglobulin or monoclonal antibodies
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How is HH8 transmitted?
- Sexual
- Blood
- Organ transplant
Discuss HH8 oncogenesis
LANA protein binds p53 & pRb
Name other HH8 virus associated cancers
- Kaposi sarcoma
– Primary effusion / body cavity lymphoma
– Multicentric Castleman’s disease
How to diagnose kaposi sarcoma?
PCR on tumor biopsy
Cancers associated with retroviruses
- Human T-leukemia virus
*Adult T-cell leukemia (ATLV)
How to treat kaposi sarcoma?
Early ART for HIV patients
Tumours caused by polyoma viruses:
- Merkel cell polyomavirus:(polyomavirus 5)
*Discovered in ~80% of Merkel cell Ca
– JC virus
*A causative link has been suggested between JC virus &
human colorectal Ca
