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!