Retroviruses and Papillomaviruses PDF

Retroviruses and Papillomaviruses Centre for Experimental Pathogen Host Research (CEPHR) [email protected] At the end of this lecture the student should be able to: my1 offimans Describe how transducing and cis activating retroviruses cause cancer in animals Describe the transmission routes and c...

Retroviruses and Papillomaviruses Centre for Experimental Pathogen Host Research (CEPHR) [email protected] At the end of this lecture the student should be able to: my1 offimans Describe how transducing and cis activating retroviruses cause cancer in animals Describe the transmission routes and clinical manifestations of HTLV-1 infection Describe the role of the HTLV-1 Tax and HBZ in infection and disease development Describe the clinical manifestations of cutaneous and tT mucosal HPV infection f Describe the role of “high risk” HPV E6 and E7 proteins in cancer development Describe prevention strategies for HPV infections Retroviridae family Delta- Human T cell leukemia virus (HTLV) gains Lentiviruses- fna w Human immunodeficiency virus (HIV) that onlyone Emit Importance of Retroviruses pinhead Human immunodeficiency virus (HIV) -AIDS Human T cell leukemia virus type 1 (HTLV-I) burden disease large - Adult T cell leukemia (ATL) and neurological conditions Molecular Biology: Reverse transcriptase (RT) virusesprovidedus V YET b Integration of Retroviral Genomes into Host Genome LTR proviralDNA LTR keystepinfertile genome integrate PEffe.at intohostileIffhiment LTR - long terminal repeat - promoter for viral gene expression - contains binding sites for cellular transcription factors - required for integration into host cell genome Three types of oncogenic retroviruses Transducing retroviruses eg RSV Cis-activating retroviruses eg MMTV onlyaffect Transactivating retroviruses eg HTLV-1 animals humans Transducing Retroviruses abnormalexpression control underLTR Eg. Rous Sarcoma virus (RSV)- Tumors in chickens in LTR Viral genes 9T src LTR genes othergenetic info v-src originated from cellular counterpart c-src giving rise To the idea that cancers might arise from abnormal expression Of normal human cellular genes Cis-Activating Retroviruses Eg. Mouse Mammary Tumor virus mycancer Promoter insertion LTR Viral genes LTR c-myc Enhancer insertion fÉd animals notcaused within proviral DNA actually enhancer near oncogene Different cellular oncogenes activated by insertion of retroviruses Close by How does HTLV-1 cause adult T cell leukemia (ATL) No cellular oncogenes No preferred integration sites Viral oncogenic proteins TAX1/HBZ Ted s Human T cell leukemia viruses (HTLVs) vFour subtypes: HTLV-1, HTLV-2, HTLV-3, HTLV-4 spreadprimatements marinnosed interspecies transmission humanhuman then Viruses. 2011 Jul;3(7):1074-90. doi: 10.3390/v3071074. Epub 2011 Jul 8. Review. Prevalence of HTLV-1 worldwide endemic in some partsofworld passedmanimmities Pract Neurol 2009;9:1 16-26 doi:10.1136/jnnp.2008.167155. HTLVs are predominantly spread by cell-to-cell Transmission Virological synapse Conduits appendages needaninfected cellnotjust vinsunits Biofilm Trans-infection Frontiers in Microbiology2012 3: 378 doi: 10.3389 HTLV-1 Transmission routes ftp ffffmmik donate ftp.exposue Ekatriates Tells Adult T cell Leukemia (ATL) i infections virus - Aggressive leukemia of CD4 +, CD8 - T cells - elevated, morphologically abnormal T cells 0T - lymphadenopathy, hepatosplenomegaly, skin lesions, hypercalcemia associated with lytic bone lesions Classification of ATL siabnormofous Ø Smoldering (5%): skin lesions abnormalTcell 19i Ø Chronic (19%): lymphadenopathy, hepatomegaly, splenomegaly, skin lesions prognosis Ø Acute ATL (59%): systemic lymphadenopathy, hepatosplenomegaly, Hypercalcemia, lytic bone lesions Smoldering iii Chronic Acute morphologically ñs characteristic phase ofacute Principles and Practice of Infectious Diseases; Sixth Edition; 2005 Papules and Plaques in a patient with ATL prolifertius henpsky HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) HAM/TSP Tithedbehormonerelated – Chronic inflammatory disease of CNS - Females in their forties - Stiff gait progressing slowly to increasing spasticity and lower extremity weakness, backpain, urinary incontinence - Non-specific brain lesions HTLV Structure HIVgp20 (gp46) (gp21) he (p19) Lin.ttn pol astgerome env (p24) (p15) Genome Structure of HTLVs gag- Core proteins IT pro- - matrix (p19) - capsid (p24) - nucleocapsid (p15) Protease - cleaves Gag and Pol polyproteins pol- Reverse transcriptase/ integrase env- Envelope proteins - surface envelope (gp46)/transmembrane (gp21) taxrexhbz- Oncogenic viral protein Viral RNA transport from nucleus to cytoplasm Counteracts the activity of Tax1 I S HTLV Lifecycle Entry: Env + Glut1/HSPG/NRP1 Rferased wantfoptphfsse uvfnfiggth.tt assembly atMembrane 0 Genome Properties of the Tax Protein binds5 LTR andanimatterpression Ø Transactivates viral gene expression Ø Immortalizes primary CD4+ cells Ø Transforms Rat fibroblasts Ø Tumors/ATL like disease in transgenic animals Feneotomontgene Pathology of Tax1 transgenic mice splenomegaly disease fhgmae model floweran Nat Med. 2006; 12:466-72. HBZ fromantisensestrand n Inhibits Tax1 mediated transactivation of viral gene expression promotes latency prevents mbaughton cosmicactivity n n Transforms primary CD4+ T cells HBZ transgenic animals develop ATL –like disease and a range of inflammatory disorders n Proliferation and maintenance of ATL cells n Only viral protein expressed in ATL cells Treatment vAZT/Interferon! + Chemotherapy v High dose chemotherapy followed by Allogenic Hematopoietic Stem Transplant fromadonor Diagnosis Serology - ELISA to detect antibodies against HTLV-1 Western Blot SNOWDRON Molecular Techniques Papillomaviridae Papillomaviruses tenures Features 00 Small non enveloped viruses factor Double stranded circular DNA E: Early canon L: Late capsidproteincoding Greater than 100 different subtypes Clinical Manifestations of HPV Infection v Squamous epithelium cells Cutaneous Mucosal Low cancer risk High cancer risk Low and high-risk cutaneous If HPV genotypes Low Risk (LR) High Risk (HR) Genotype 1, 2, 3, 4, 10, 27, 28, 41, 57, 65 5, 8 Clinical manifestation Benign cutaneous warts Epidermodysplasia verruciformis (EV) Transmission route Fomites, dead skin Genetic susceptibility, UV Cutaneous HPV Infections Low risk (LR) - Benign skin warts regressovertime unusualtosee adultwarts High risk (HR) - Epidermodypasia verruciformis (EV) Flat or scaly red/brown warts Skin cancer later in life widespread canbecome andGotregress Low and high-risk mucosal HPV genotypes e Low Risk (LR) High Risk (HR) Genotype 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 Clinical manifestation Genital warts Benign cervical changes Cervical cancer Oropharynx cancer Anus, Penile, vulvar and vaginal cancers Transmission route Sexual transmission Genital Warts lowriskof instancer progress Very prevalent in sexually active adults HPV-6 and 11 Self-limited, regress spontaneously or persist for years Difficult to treat in immunosuppressed patients and in pregnant women Imiquimod; stimulation of innate and acquired immune response Contribution of Mucosal HR HPV to cancers HPV 16, 18, 31, 33, 45, 52, 58 Increased prevalence of oropharynx cancer due to HPV infection HPV+ oropharynx cancers 2.8% new cancer cases and over 8,000 deaths in 2015 Most cases related to HPV Implications of HPV positive Oropharynx cancers Younger age at diagnosis and sexual behavior Better response to treatment involving combined surgery and radiation or chemotherapy Lower rates of disease relapse Improved overall survival Swiecicki et al ; 2016 World J Clin Oncol 7: 15-26 Cervical Cancer Common malignancy among women worldwide 80% of cases occur in developing countries Sexually transmitted disease HPV 16, 18, 31, 45 Lifecycle of HPVs c get EÉEn repiffffentiation offsamous ite N ENGL J MED 361;3 2009 Existp ideation Cellular events leading to cervical cancer Cervical intraepithelium neoplasia (CIN)- CIN 1, 2, 3 correspond to mild, moderate and severe dysplasia CIN 3 severe mostepi replacedby infected basal cells Papanicolaou (Pap) smear determines the presence of exfoliated basal epithelial cells variableenstegression prestigious Fields Virology: Chapter 62 Pathogenesis of cervical cancer caused by HPV Persistent infection Integration of Oncogenic viral genes E6 and E7 into host genome resulting in persistent expression throughout cervical epithelium Inactivate cellular tumor suppressor proteins Adhd including p53, Rb etc De-regulate cell cycle Genome instability and aneuploidy Abnormal growth and survival of infected cells Koilocyte Abnormal squamous epithelium cell as a result of infection with HR HPV Enlarged nucleus Clearing “halo” around the nucleus Condensed chromatin Immunity against HPVs Antibody response against viral capsid proteins L1 and L2 Anti–L1 antibodies are virus neutralizing and type specific Anti-L2 are generated but not as potent as anti-L1 capsidproteins containepitopesforneutralizing antibodies Specific cell mediated immune response can trigger clearance of natural HPV infection HPV Vaccination Expression of L1 in tissue culture leads to the formation of virus like particles with the same conformation dependent neutralizing epitopes as the natural virus Intramuscular injection Highly immunogenic generating high levels of neutralizing antibodies; safe and well tolerated Vaccines Gardasil 9 2015 (HPV 6/11/16/18/31/33/45/52/58) used in Ireland for girls and boys subtipes 9diff Joura and Pils, 2016. Clinical Microbiology and Infection 22: S125-S127 highuptake Summary Ø Low risk HPVs causes benign warts Ø High risk genotypes gives rise to cervical cancer Ø Oncogenic proteins E6 and E7 Ø Safe effective vaccine available Summary :HTLV-1 and HPV Chronic infection Host/Viral interactions Oncogenic- HTLV-1 –Adult T cell leukemia HPV- Cervical cancer AND other cancers Oncogenic proteins: Tax 1- HTLV E6/E7/E5-HPV References Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer. 2007 Apr;7(4):270-80. Matsuoka M and Jeang KT Arbyn and Dillner: HPV Vaccination; Journal of Clinical Virology 2007 189-197 Munger et al, 2004: Mechanisms of Human Papillomavirus-Induced Oncogenesis Journal of Virology, 78, 11451-11460 Joura et al Broad Spectrum HPV Vaccine Study. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015 Feb 19;372(8):711-23. doi: 10.1056/NEJMoa1405044.