hiv associated tumour viruses : partners in crime · viral oncogenesis •progression (...
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HIV associated tumour viruses : Partners in Crime
Dr. Annelle Zietsman
16 August 2019
Viral oncogenesis
• Viruses cause 10 – 15 % of human cancers
• Chronic infections - chronic inflammation - cancer
• Viral infection - genetic mutation + host immune deficiency +- more viral infections - malignancy
• Mechanism 1 :
• direct transformation where viruses express viral oncogenes that can directly transform infected cells - inactivates p53 ( tumour suppressor gene )
Viral oncogenesis
• Mechanism 2 :
• several viruses encode oncoproteins that employ mechanisms to inactivate 2 of the major regulators of genome stability : cell viability and cell cycle - inactivates p 53 and inhibits apoptosis ( programmed cell death )
• Mechanism 3 :
• DNA damage : chronic infection - inflammation - DNA damage
• inflammation and DNA damage induced by co-infections eg. STD’s as well as alcohol and smoking eg. Ca cervix
Viral oncogenesis
• Mechanism 4 :
• integration of viral DNA into the host genome
• 4 stages of carcinogenesis :
• Initiation ( reversible ) :
• mutation , transversion , transition and DNA-deletion
• Promotion ( reversible ):
• mutated cell is stimulated to grow and divide faster – becomes a population of cells no DNA changes
Viral oncogenesis
• Progression ( irreversible ) :
• growth and expansion of tumour cells over normal cells and additional mutations ( karyotypic instability )
• Malignant conversion and growth
• Process can take many years
• 3 molecular targets are :
• proto-oncogenes , cellular oncogenes ,tumour suppressor genes
Carcinogenic ( Oncogenic ) viruses
• Since November 2016 HIV 1 is officially listed as a carcinogen by IARC
• it does not directly cause cancer ; but is a cancer hazard
• HIV + 2nd co- virus - cancer
• RNA viruses : HTLV – 1, 2 and 3
• HEP C
• DNA viruses : HPV
• EBV
• HHV 8 / KSHV
• HEP B and MCV
Oncogenic viruses
• RNA retroviruses :
• After infecting the cell , retroviruses are reverse – transcribed into provirus DNA ; then incorporated into host genome ( DNA )
• Human T-cell lymphotropic virus :
• HTLV -1 : lymphoblastic leukemia
• HTLV – 2 : T- cell lymphoma and HCL
• HTLV – 3 : high grade B-cell lymphoma but can also stimulate proliferation of KS cells
• HEP C : hepatocellular carcinoma
Oncogenic viruses
• DNA viruses :
• insertional mutagenesis : viral DNA is inserted into host genome and disrupts normal growth control
• Oncogenic DNA viral genes code for proteins that affect growth regulating substances in cell
• interfere with cellular inhibitors of growth – uncontrolled cell replication
• causes gene translocation and rearrangement eg. Cmyc in Burkitt’s
Oncogenic viruses
• HPV ( Human papilloma virus ) :
Mucosal HPV :
• Ca cervix - subtypes 16 , 18
• oral SCC - subtype 16
• anal , vaginal and vulva SCC
• Genital warts caused by subtypes 6, 11
• Best Rx is prevention - Vaccinate please
• Cutaneous HPV : subtypes 5, 8
• conjunctiva SCC ( HIV ) and skin SCC ( post – transplant )
Oncogenic viruses
• EBV ( Epstein Barr virus ) or HHV 4 : increase risk 60 – 200 fold
• EBV infects B- lymphocytes and nasopharynx epithelium ; when EBV – infected cells are exposed to infection eg. Malaria - can cause malignancy
• lymphomas eg. Burkitt’s lymphoma , DLBCL , primary CNS lymphoma
• Hodgkins lymphoma
• nasopharynx ca
• gastric ca
• cutaneous T-cell lymphoma ( + HTLV – 1 )
Oncogenic viruses
• HHV 8 ( KSHV ) :
• HIV associated Kaposi sarcoma
• organ transplant KS
• classic KS ( HIV negative )
• MCD ( multicentric Castleman’s disease )
• PEL ( primary effusions lymphoma )
• ? angiosarcoma
Oncogenic viruses
• HHV - 8 :
• HHV – 8 infection of vascular endothelial cells result in a change to spindle cell morphology - proliferating angiogenic KS lesion
• HIV infection induces inflammatory cytokine response ; with secretion of IL – 6 , TNF alpha etc.
• these cytokines serve as growth factors for endothelial cells infected with HHV- 8 - spindle cell changes - KS
• HIV infected mononuclear cells secrete angiogenic factors eg. Fibroblast GF and VEGF ( vascular endothelial GF ) - induces the profuse vascular tissue and fibrosis so typical of KS
Oncogenic viruses
• HHV - 8 :
• HHV – 8 has genes that encode a viral IL – 6 ( Interleukin – 6 ) and other proteins that contribute to growth of KS and metastatic spread
• Hep B :
• Hep B + patients have 25 – 40 % higher risk of liver ca ( HCC )
• Rx : prevention eg. Vaccination
• Interferon / Tenofovir / Entecavir
Oncogenic viruses
• MCV ( Merkel cell polyoma virus ) :
• Merkel cell skin cancer = neuro-endocrine skin cancer that is lethal and metastasizes early
• CMV :
• causal factor in some colorectal ca’s ? need underlying inflammatory bowel disease
• ? Muco-epidermoid salivary gland ca’s
• Parvovirus B 19 :
• aplastic anemia / red cell aplasia
Treatment
• Prevention :
• Education and creating awareness
• Prevention of HIV
• Vaccination : HPV
• Hep B
• Early detection :
• Education and creating awareness
• Screening eg. Ca Cx Pap smears
Treatment
• Medical treatment :
• HAART : keep CD 4 count > 350 – can prevent KS
• does not prevent lymphoma etc.
• ? Antivirals eg. Ganciclovir
• Cancer Rx’s of lymphomas, KS , ca cervix
• Surgery ; Radiotherapy ; Chemotherapy ; Biologicals eg. Rituximab in MCD and lymphoma
• Palliative and supportive care - multidisciplinary team
Thank you!