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Lecture 3 virology

Lecture 3 virology. Carcinogenesis. Carcinogenesis.

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Lecture 3 virology

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  1. Lecture 3 virology Carcinogenesis

  2. Carcinogenesis • Carcinogenesis or Oncogenesis = creation of cancer= normal cells are transformed into cancer cells= characterized by a progression of changes on cellular and genetic level that ultimately reprogram a cell to undergo uncontrolled cell division, thus forming a malignant mass. • Many causes of cancer: • *There are about 200 different types of cancer. They can start in any type of body tissue. • What affects one body tissue may not affect another. For example, tobacco smoke that you breathe in may help to cause lung cancer. Overexposing your skin to the sun could cause a melanoma on your leg. But the sun won't give you lung cancer and smoking won't give you melanoma. • **Apart from infectious diseases, most illnesses are 'multifactorial'. Cancer is no exception. In other words, there is no single cause for any one type of cancer.

  3. Causes of Cancers • There are many different kinds of cancers. • Cancer can develop in almost any organ or tissue, such as the lung, colon, breast, skin, bones, or nerve tissue. • There are many causes of cancers, including: • 1..Benzene and other chemicals • 2..Certain poisonous mushrooms and a type of poison that can grow on peanut plants (aflatoxins) • 3..Certain viruses • 4..Radiation • 5..Sunlight • 6..Tobacco • However, the cause of many cancers remains unknown.

  4. @ In general, if we are exposed to chronic infection, injury, pollution, unhealthy food, water air, tobacco and drug abuse, etc… over many years, our risk of developing cancer increases markedly. @@We are all actually swimming in the sea of germs all through our life:::::::::::::::::: Only few of us get the disease,,,,,,, while others resist the germs successfully.

  5. Multistep carcinogenesis • Multiple genetic changes must occur to convert a normal cell into a malignant one . • Intermediate stages = transformation / immortalization / Hyperplasia and preneoplasia . • Cancer =multistep process of cellular evolution , probably involving repeated selection of rare cells withsome selection of growth advantage . • Cancer development requires several ‘assaults’ on an individual cell; The number (range )of mutations underlying this process=3-8 . • To transform into a cancer cell =a series of changes which slowly release the cell from the multiple checks and balances which control its normal growth.===involves both genetic changes and environmental factors,,,,,,, • Explains why cancer may take many years to develop after exposure to a single risk factor • Therefore generally a disease of middle and old age.

  6. Multistep Carcinogenesis • Tumor viruses= usually acts as a cofactor providing only some of the steps required to generate malignant cells . • Tumor viruses= necessary but not sufficient for tumor with viral etiology . • Tumor viruses=initiators of neoplastic process .

  7. HUMAN CANCER VIRUSES

  8. HUMAN CANCER VIRUSES • It is generally agreed that viruses are involved in 10–20% of all cancers . • Viruses are etiologic factors in the development of several types of human tumors , including 2 of great significance world wide :- • 1- Cervical cancer by human Papiloma virus . • 2- Liver cancer by Hepatitis B & c virus . • A limited amount of genetic information ( one or a few viral genes ) of a tumor virus can profoundly alter the growth behavior of cell into a neoplastic one .

  9. NO characteristic Size ,shape , chemical composition Many species & Families 2 Cause benign & malignant tumors • e 3 Most recognized tumor viruses have RNA genome from which a DNA provirus is formed after infection of cells ( HCV is an exception) Tumor viruses 1 6 4 Common Occurrence In Animal Tumors but only few viruses Associated with human tumors 5 More :- 1- Rapid ,2-Reliable ,3-Efficient (tumor producer ) 4- Readily analyzed role of cancer

  10. ** Mechanisms:Some commonality among viruses that cause tumors= tumor viruses change cells by integrating their genetic material with the host cell's DNA. This is a permanent insertion in that the genetic material is never "removed."The insertion mechanism can differ= depending on whether the genetic material in the virus is DNA or RNA. DNA TUMOR viruses  ( encode viral oncoproteins ) 1..Affect cellular growth control pathways 2… important for viral replication . RNA Tumor viruses (( Retrovirus )) carry reverse transcriptase  DNA copy  integrate 1- Highly oncogenic ( direct – transforming ) v. = cellular oncogenes . 2- Weakly oncogenic ( slowly – Transforming ) v. . 3- Indirect CANCER Inducers = HC V .

  11. Linkages:The link between viruses and cancerwas one of the pivotal discoveries incancer research

  12. Many people can be infected with a cancer- causing virus, and never get cancer. The virus only causes cancer in certain situations. Many women get a high risk HPV infection, but never develop cervical cancer. Another example is Epstein-Barr virus (EBV). Most people are infected with EBV,,,But who catch it late in life get glandular fever and have an increased risk of lymphoma • Cancer is not an infectious disease like tuberculosis, typhoid, cholera, pneumonia, etc. It does not spread by contact. • It is not caused by any germs coming from outside. • Viruses can help to cause some cancers. But this does not mean that these cancers can be caught like an infection. • What happens is that the virus can cause genetic changes in cells that make them more likely to become cancerous.

  13. Transmission of Tumor viruses • 1- Vertical Transmission : 1# virus genetic material in the sprem or the egg . 2# VIRUS PASSED ACROSS PLACENTA . 3# Virus transmitted in the breast milk . Expression to virus early in life can result in tolerance to viral Ags  I.R not eliminate the virus  large amount of virus produced  high frequency of cancer occurs .

  14. 2..Horizontal Transmission • Probably does not occur in humans . • Evidence = close contacts with cancer patients do not have increased freguncy of cancer . • Rare Random Event  if occur .

  15. DNA Tumor Viruses

  16. Polyomaviridae

  17. Polyomaviridae

  18. Genome Genomes divided into two regions, early and late Early proteins LT, MT and sT antigens expressed from differentially spliced mRNAs Late, capsid proteins VP1, VP2 and VP3 (viral capsid) BKV and JCV : 75% (nucleotide sequence Homology) 70% with SV40

  19. Potentiallyoncogenic (tumor-causing) • Persist as latent infections without causing disease • They may produce tumors in a host of a different species, or a host with an ineffective immune system • The name polyoma refers to the viruses' ability to produce multiple (poly-) tumors (-oma)

  20. Polyomaviruses,Host,Cellreceptor,Tissuetropism,Disease *seen in bone marrow transplant recipients. ** seen in renal transplant recipients. ***Primarily seen in AIDS patients

  21. Pathogenesis Immunocompromised

  22. PML Fatal demyelinating disease of the white matter and involves multiple areas of the brain. The clinical picture includes visual field defects, mental status changes and weakness. The disease rapidly progresses to blindness, dementia and coma, and most patients die within 6 months. Diagnosis: CT or MRI lumbar puncture for JCV PCR Treatment: Cidofovir may be beneficial. highly active antiretroviral therapy( HAART) in AIDS patients

  23. BK nephropathy: no evidence that BKV causes disease in the immune competent population possible route of infection through contaminated food or water or respiratory spread remains latent in lymphocytes, urogenital tract, and brain but may be reactivated if the host becomes immunocompromised. especially associated with disease in renal transplant patients; thought to cause graft failure in 2-5% of this population treatment is to decrease immunosuppression as much as possible without causing rejection Cidofovir appears to reduce BKV-associated nephropathy viral inclusions and cellular changes in BK nephropathy are seen in tubular epithelium of a renal transplant case

  24. Human Papilloma Virus (HPV)

  25. Human Papilloma Virus (HPV) • How common is human papillomavirus (HPV) infection? • HPV is the most common sexually transmitted infection in the United States. Currently, more than 20 million men and women in the United States are infected with HPV, and more than 6 million are estimated to become infected each year. HPV is most common in young women and men in their late teens and early 20s. By age 50, at least 80 percent of sexually active women will have acquired HPV infection.

  26. How serious is disease caused by HPV? • HPV infection can lead to cervical cancer in women as well as to other cancers that can affect males or females. • Cervical cancer is diagnosed in more than 9,700 women each year in the United States each year and causes 3,700 deaths====== Seventy percent of cervical cancers are caused by strains of HPV included in the newly licensed HPV vaccine. • HPV also causes Genital warts in men and women.

  27. HPV-INDUCED CANCERS

  28. Papillomaviridae • Papilloma virus can infect broad spectrum of vertebrates ( human , animals ,rabbits …..etc ). • HPV had been implicated in the pathogenesis of HUMAN oral , laryngeal nasopharyngeal and cervical warty carcinomatous lesions . • HOST Vertebrate CELL TROPISM : Epithelial cells of skin & mucous membranes

  29. VIRION Non-enveloped. Small, icosahedral, about 52-55 nm in size. A single molecule of circular dsDNA is contained within the capsid, which is composed of 72 pentamers arranged on a T = 7 lattice. GENOME Circular dsDNA, about 8 kb in size, associated with cellular histones in a chromatin-like complex.

  30. NUCLEAR Replication is divided in two distinct steps that are linked to the differentiation state of the host epithelial cell: The plasmid replication The vegetative replication • REPLICATION:

  31. A) The plasmid replication • takes place in the basal squamous epithelial cells. It corresponds to viral DNA replication in synchrony with the host cell chromosome in order to ensure an average of one viral genome per basal cell. • 1..Virus attaches to host receptors and is endocytosed into vesicles in the basal squamous epithelial cell. • 2..Transport to the nucleus and uncoating of the viral DNA. • 3..Early-region transcription and translation of the early proteins. • 4..Steady-state viral DNA nuclear replication. Requires the viral E1 and E2 proteins .

  32. B) The vegetative replication • Which occurs in differentiated keratinocytes. In these cells, which no longer undergo cellular DNA synthesis, there is a burst of viral DNA synthesis with active production of virions. • 1..Vegetative viral DNA synthesis. • 2..Transcription of the late region. • 3..Capsid proteins L1 and L2 synthesis. • 4..Assembly of the virion particles. • 5..Nuclear breakdown and release of viruses.

  33. Basic virology of human papilloma virus • A- HPV structure • Small ( 55-60 nm ) • Icosahedral ( cubic ) symmetry . • Capsid = 72 capsomere • DNA genome . • Non enveloped – stable / infectious . • Resistant to : • Heat . • Organic solvents . • Therapeutic agents . • E6 + E 7= (Onco-proteins )

  34. Carcinogenic potential OF DIFFERENT HPV types High risk types ( 15 types ) : HPV 16 , 18 , 31 , 33 ,35 , 39 , 45 , 51 , 52 ,56 ,58 ,68,73 , 82 . Probable ( Moderate ) risk types (3 types) : HPV 26 , 53 ,66. Low risk types (12 types ):HPV 6, 11 , 40 , 42 , 43 ,44 ,54 , 61,70, 72 ,81 . Location of lesion: Mucosal types ( > 40 types ) : Genital and non genital areas like airways , conjunctiva . Cutaneous types .

  35. Papiloma viral replication cycle • Papova viruses undergo 2 types of interactions with the host cells : - • 1- Permissive cells  viral replication  synthesis of progeny of virus  cell death ( lysis) . • 2- Non permissive cells  no replication ( = chronic and latent infections ) transformation  integration of viral genes with host genomes  altered cellular phenotype  no virus progeny produced .

  36. Pathogenesis • HPV infections === 1- As a rule : Latent and persistent ( without clinical manifestation ) 2- As an exception : clinically expressed disease : A- Most HPV infections : minor manifestations  resolved quickly . B- minority  HPV persistence  either: • Condylomas ( Benin lesions ) warts . • Cancer –precursor lesions . • Invasive cancers .

  37. Transmission of HPV • Transmitted environmentally or by casual skin to skin contact ,and there are separate group of about 30 HPV are typically transmitted through sexual contact

  38. Transmission of HPV • A) As a rule  Mechanical trauma through : • 1-Sexual transmission : > 20 million American are infected by this way . • 2-Extra genital transmission:oral , oropharyngeal , conjunctiva , nose ,laryngeal and esophagus . • 3-Fomite transmission: sex toys , examination tools , towels, and underwear . • B)Vertical transmission : mother to infants during child birth:Best example : juvenile Rec-Resp- papillomata RRP by HPV 6 and 11 .

  39. Prevention & Control

  40. Vaccination • To prevent HPV infection • Antibody to one of the HPV types cross reactive with other HPV types . • Well preserved L1 gene  target of vaccination production strategies .

  41. Vaccination • Well preserved L1 gene  target of vaccination production strategies . • A variety of HPV vaccines may provide immunity (neutralizing antibodies) to a combination of high-risk or high- and low-risk HPV types’ • In 2006, the FDA licensed a quadrivalent, prophylactic HPV vaccine which is designed to reduce the incidence of cervical cancer caused by HPV 16 and 18 and vulvar condylomas by HPV6 and 11. • It offers protection for up to 5 years after vaccination; However it does not eliminate the risk of cervical cancer due to presence of other oncogenic HPV types.

  42. Two HPV vaccines: Cervarix (GSK) and Gardasil (Merck): • Cervarix is an inactivated bivalent vaccine that protects against HPV types 16 and 18. • Gardasil is an inactivated quadrivalent vaccine that protects against HPV types 16 and 18, and also against types 6 and 11, which are human papillomaviruses that cause genital warts.

  43. ` Epstein Barr Virus (EBV)

  44. EBV is associated with: 1-Burrkits lymphoma:cancerof thlymphatic system (in particular, B lymphocytes). 2-nasopharyngeal carcinoma. 3-B-cell lymphomas. 4- Hodgkin's lymphoma

  45. Picture of a mouth of a patient with Burkitt's lymphoma showing disruption of teeth Seven-year-old Nigerian boy with a several month history of jaw swellnig which had been treated with antibiotics. The tumor was ulcerated and draining.

  46. Cytomegalovirus (CMV)

  47. Mechanism of Cell transformation • Human CMV induced oncomodulation may result from the activity of virus regulatory proteins and noncoding RNA, which influence properties of tumor cells including cell proliferation, survival, invasion, production of angiogenic factors, and immunogenicity. • As a result, HCMV infection may lead to a shift to a more malignant phenotype of tumor cells and tumor progression

  48. HCMV gene products have been reported to be involved in: • cell cycle dysfunction, • genome instability, • cell immortalization, • inhibition of important cellular players involved in apoptosis and immune invasion 

  49. Other gene products with oncogenic potential are immediate early (IE) 1 and IE2. The unconventional “hit and run” mechanism has been proposed to explain the transformation by IE1/IE2.

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