An introduction to virology
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This document provides an overview of virology and viral replication. It begins with an outline of topics to be covered, including the structure and classification of viruses, basic virology, and clinical virology. It then discusses viral structure, noting there are five basic types. Viral replication is summarized in seven steps: adsorption, entry, uncoating, transcription, synthesis of viral components, assembly, and release. Control methods involve knowledge of reservoirs, transmission, inactivation methods, vaccines, antiviral drugs, and drug resistance. Emerging viral diseases and some examples are also mentioned.
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An introduction to virology
- 1. 1
- 2. VIROLOGY (The study of Viruses) 2 Dr. Kaveh Haratian Department of Microbiology and Immunology Alborz University of Medical Sciences Fall 1394
- 3. 3 OUTLINE • introduction to viruses structure and classification • basic virology • clinical virology
- 4. In VIROLOGY we notice: different structure different method of replication implications for diagnosis treatment prevention 4
- 5. CONTROL METHODS INVOLVE KNOWLEDGE OF: RESERVOIRS MODE OF TRANSMISSION METHODS TO INACTIVATE VIRUS OF INTEREST VACCINES ANTI-VIRAL DRUGS DEVELOPMENT OF DRUG RESISTANCE 5
- 6. EMERGING VIRAL DISEASES Some new global examples: HIV/AIDS Hantavirus pulmonary syndrome (HPS) West Nile encephalitis (WNV) Severe acute respiratory syndrome (SARS) Monkey pox Human metapneumovirus Ebola hemorrhagic disease 6
- 7. Consequences of viral infections 50% of all absenteeism Children: 7 or more viral infections per year that involve a visit to a physician 7
- 8. Consequences of viral infections Suffering, followed by recovery Persistent disease Fatal disease Congenital disease Contributory factor in cancer Contributory factor in other diseases 8
- 10. VIRUSES CAN BE USEFUL VACCINE DEVELOPMENT GENE THERAPY TOOLS TO INVESTIGATE HOST CELLS 10
- 11. WHAT ARE VIRUSES? 11 “A PIECE OF BAD NEWS WRAPPED UP IN A PROTEIN”
- 12. WHAT ARE VIRUSES? NUCLEIC ACID GENOME: DNA OR RNA PROTEIN COAT PROTECTION, ENTRY LIPID ENVELOPE IN SOME VIRUSES SMALL (20-400nm) OBLIGATE INTRACELLULAR PARASITES 12
- 13. 13 Virus particle = virion White, DO and Fenner, FJ. Medical Virology, 4th Ed. 1994
- 14. 14Koneman et al. Color Atlas and Textbook of Microbiology 5th Ed. 1997
- 15. Virus versus Virion Virus is a broad general term for any aspect of the infectious agent and includes: • the infectious or inactivated virus particle • viral nucleic acid and protein in the infected cell Virion is the physical particle in the extra- cellular phase which is able to spread to new host cells; complete intact virus particle
- 16. 16 Growth on artificial media Division by binary fission Contain DNA and RNA Contain protein synthesi s machine ry Contain muramic acid Sensitiv e to antibioti cs Bacteria often yes yes yes often yes Viruses never no Either DNA or RNA no* no no * The arenavirus family appears to ‘accidentally’ package ribosomes, but these appear to play no role in protein synthesis.
- 17. CONSEQUENCES NO BROAD RANGE ANTIBIOTICS HEAVILY PARASITIC ON HOST CELL NEED TO LOOK FOR WEAK LINK 17
- 18. HOST RANGE MAY BE WIDE OR NARROW MAY BE INSECT/ANIMAL, INSECT/PLANT DO NOT CROSS EUCARYOTE / PROCARYOTE BOUNDARY 18
- 19. 19 FACTORS AFFECTING HOST RANGE - CELL SURFACE RECEPTORS
- 20. FACTORS AFFECTING HOST RANGE CELL SURFACE RECEPTORS 20 • AVAILABILITY OF REPLICATION MACHINERY • ABILITY TO GET OUT OF CELL AND SPREAD • HOST ANTI-VIRAL RESPONSE
- 21. VIRAL STRUCTURE : SOME TERMINOLOGY virus particle = virion protein which coats the genome = capsid capsid usually symmetrical capsid + genome = nucleocapsid may have an envelope 21
- 22. ICOSAHEDRAL SYMMETRY 20 faces 12 vertices 22 http://www.tulane.edu/~dmsander/WWW/Video/Video.html
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- 30. 30
- 31. 31
- 32. 32 Adenovirus
- 33. 33
- 34. 34
- 35. 35 Adenovirus
- 36. 36
- 38. SYMMETRY OF NUCLEOCAPSID ICOSAHEDRAL HELICAL 38
- 39. TOBACCO MOSAIC VIRUS 39 adapted from: Klug and Caspar Adv. Virus Res. 7:225
- 40. 40
- 41. Helical symmetry Length controlled by nucleic acid Helix may be stiff or flexible 41
- 42. 42
- 43. 43
- 45. ENVELOPE OBTAINED BY BUDDING THROUGH A CELLULAR MEMBRANE (except poxviruses) POSSIBILITY OF EXITING CELL WITHOUT KILLING IT CONTAINS AT LEAST ONE VIRALLY CODED PROTEIN 45
- 46. 46
- 47. ENVELOPE OBTAINED BY BUDDING THROUGH A CELLULAR MEMBRANE (except poxviruses) POSSIBILITY OF EXITING CELL WITHOUT KILLING IT CONTAINS AT LEAST ONE VIRALLY CODED PROTEIN ATTACHMENT PROTEIN LOSS OF ENVELOPE RESULTS IN LOSS OF INFECTIVITY 47
- 48. ENVELOPE 48
- 49. 5 BASIC TYPES OF VIRAL STRUCTURE 49 HELICAL ENVELOPED HELICAL ENVELOPED ICOSAHEDRAL COMPLEX ICOSAHEDRAL Adapted from Schaechter et al., Mechanisms of Microbial Disease nucleocapsidicosahedral nucleocapsid nucleocapsid helical nucleocapsid lipid bilayer lipid bilayer glycoprotein spikes = peplomers
- 50. UNCONVENTIONAL AGENTS VIROIDS RNA only Small genome Do not code for protein So far, only known viroids are in plants 50 • hepatitis delta agent - some viroid, some virus features
- 51. UNCONVENTIONAL AGENTS PRIONS protein only? do not contain any nucleic acid? 51
- 53. CLASSIFICATION BASIC STRUCTURE AND MOLECULAR BIOLOGY particularly important as diagnostic and therapeutic abilities expand past schemes host range tissue infected type of cell infected mode of transmission disease caused 53 Arboviruses (arthropod borne)
- 54. CLASSIFICATION NUCLEIC ACID CAPSID PRESENCE OF ENVELOPE REPLICATION STRATEGY 54
- 55. CLASSIFICATION NUCLEIC ACID RNA or DNA segmented or non-segmented linear or circular single-stranded or double-stranded if single-stranded is genome mRNA (+) sense or complementary to mRNA (-) sense 55
- 56. symmetry icosahedral, helical, complex enveloped or non-enveloped number of capsomers 56 CLASSIFICATION CAPSID
- 57. CLASSIFICATION ENVELOPE REPLICATION STRATEGY 57
- 58. 58 HERPESVIRIDAE HEPADNAVIRIDAE ENVELOPED PAPILLOMAVIRIDAE POLYOMAVIRIDAE (formerly grouped together as the PAPOVAVIRIDAE) CIRCULAR ADENOVIRIDAE LINEAR NON-ENVELOPED DOUBLE STRANDED PARVOVIRIDAE SINGLE STRANDED NON-ENVELOPED POXVIRIDAE COMPLEX ENVELOPED DNA VIRUSES Modified from Volk et al., Essentials of Medical Microbiology, 4th Ed. 1991 All families shown are icosahedral except for poxviruses
- 59. 59 FLAVIVIRIDAE TOGAVIRIDAE RETROVIRIDAE ICOSAHEDRAL CORONAVIRIDAE HELICAL ENVELOPED ICOSAHEDRAL PICORNAVIRIDAE CALICIVIRIDAE NONENVELOPED SINGLE STRANDED positive sense BUNYAVIRIDAE ARENAVIRIDAE ORTHOMYXOVIRIDAE PARAMYXOVIRIDAE RHABDOVIRIDAE FILOVIRIDAE SINGLE STRANDED negative sense REOVIRIDAE DOUBLE STRANDED RNA VIRUSES ENVELOPED HELICAL ICOSAHEDRAL NONENVELOPED Modified from Volk et al., Essentials of Medical Microbiology, 4th Ed. 1991
- 60. Adenovirus
- 61. Herpesviridae
- 62. Influenza Virus
- 63. Smallpox Virus
- 64. Virus Classification Historically based on: Host preference: Plant, insect, animal, human Target organ: respiratory, hepatic, enteric, etc. Vector: arboviruses Overlapping, inconsistent Currently based on molecular biology of genome and biophysical structure
- 65. Virus Classification Viruses with similar structural, genomic & replication properties are grouped into families (suffix: viridae) e.g. Herpesviridae Families subdivided into genera (suffix: virus) e.g. Herpes simplex virus, Cytomegalovirus, Varicella zoster virus Subtypes based on nucleotide sequence and antigenic reactivities e.g. Herpes simplex virus type 1, Herpes simplex virus type 2
- 66. Virus Classification Viruses Nucleic acid: DNA RNA Envelope: Yes No Symmetry: Cubic Helical (Icosahedral) (Cylindrical)
- 67. Classification of Some Common Viruses Family Viruses Type of Nucleic Acid Envelope Capsid Symmetry Picornaviridae Enteroviruses, polio, hep. A ss (+) RNA No I Caliciviridae Norwalk virus ss (+) RNA No I Togaviridae Rubella ss (+) RNA Yes I Rhabodoviridae Rabies ss (+) RNA Yes H Paramyxoviridae Parainfluenza, RSV, measles, mumps ss (-) RNA Yes H Orthomyxoviridae Influenza ss (-) RNA Yes H Retroviridae HIV 1,2, HTL I,II ss (+) RNA Yes I Hepadnaviridae Hepatitis B ds DNA Yes Unknown Parvoviridae Parovirus B - 19 ss (+) or (-) DNA No I Adenoviridae Adenovirus ds DNA No I Herpesviridae HSV, CMV, EBV, VZV, HHV6 ds DNA Yes I I = icosahedral, H = helical
- 68. Virus Classification (Common) DNA RNA Hepatitis B Human Papilloma Virus Parvovirus B19 Adenovirus Herpesviridae Polyomaviruses Influenza RSV Parainfluenza Hepatitis A, C, D, E Enteroviruses Encephalitis viruses Measles, Mumps, Rubella Norwalk, Rotavirus Virtually all others
- 69. BASIC STEPS IN VIRAL LIFE CYCLE ADSORPTION PENETRATION UNCOATING AND ECLIPSE SYNTHESIS OF VIRAL NUCLEIC ACID AND PROTEIN ASSEMBLY (maturation) RELEASE 69
- 70. ADSORPTION 70
- 71. ADSORPTION TEMPERATURE INDEPENDENT REQUIRES VIRAL ATTACHMENT PROTEIN CELLULAR RECEPTORS 71
- 72. - ENVELOPED VIRUSES •FUSION WITH PLASMA MEMBRANE •ENTRY VIA ENDOSOMES 72
- 74. - ENVELOPED VIRUSES •FUSION WITH PLASMA MEMBRANE •ENTRY VIA ENDOSOMES, FUSION WITH ACIDIC ENDOSOME MEMBRANE 74
- 75. 75
- 76. 76
- 77. PENETRATION - ENVELOPED VIRUSES 77 from Schaechter et al, Mechanisms of Microbial Disease, 3rd ed, 1998
- 78. VIRUS UPTAKE VIA ENDOSOMES CALLED VIROPEXIS / ENDOCYTOSIS / PINOCYTOSIS 78
- 80. PENETRATION NON-ENVELOPED VIRUSES 80 entry directly across plasma membrane:
- 81. 81
- 82. UNCOATING NEED TO MAKE GENOME AVAILABLE ONCE UNCOATING OCCURS, ENTER ECLIPSE PHASE ECLIPSE PHASE LASTS UNTIL FIRST NEW VIRUS PARTICLE FORMED 82
- 83. SYNTHESIS OF VIRAL NUCLEIC ACID AND PROTEIN MANY STRATEGIES NUCLEIC ACID MAY BE MADE IN NUCLEUS OR CYTOPLASM PROTEIN SYNTHESIS IS ALWAYS IN THE CYTOPLASM 83
- 84. ASSEMBLY AND MATURATION NUCLEUS CYTOPLASM AT MEMBRANE 84
- 85. smallpox virus cytoplasmic assembly and maturation 85 F. A. Murphy, School of Veterinary Medicine, University of California, Davis. http://www.vetnet.ucdavis.edu/fam_graphics/download.html
- 86. RELEASE LYSIS BUDDING THROUGH PLASMA MEMBRANE NOT EVERY RELEASED VIRION IS INFECTIOUS 86
- 87. HIV budding and maturation 87Hsiung, GD et al., Diagnostic Virology 1994 p204 (D. Medina)
- 88. HIV – mature form 88 Briggs JA et al. Structure. (2006) 14:15-20
- 89. Viral Replication i) adsorption (attachment) ii) entry iii) uncoating iv) transcription v) synthesis of virus components vi) assembly vii) release
- 90. Viral Replication i) Adsorption (attachment): random collision interaction between specific proteins on viral surface and specific receptors on target cell membrane (tropism) not all cells carrying a receptor for a particular virus can be productively infected by that virus
- 91. Viral Replication i) Adsorption (attachment): some viruses may use more than one host cell receptor (e.g. HIV) able to infect a limited spectrum of cell types (host range) most neutralizing antibodies are specific for virion attachment proteins
- 92. Viral Replication ii) Entry (penetration): 2 mechanisms - endocytosis - fusion of virus envelope with cell membrane iii) Uncoating: release of viral genome cell enzymes (lysosomes) strip off the virus protein coat virion can no longer be detected; known as the “eclipse period”
- 93. Viral Replication iv) Transcription/Translation/Synthesis: a) DNA viruses: • replicate their DNA in host cell nucleus mediated by viral enzymes • synthesize capsid and other proteins in cytoplasm using host cell enzymes • new viral proteins move to nucleus where they combine with new DNA to form new viruses • Exception - Poxviruses synthesize their parts in host cell’s cytoplasm
- 94. Viral Replication iv) Transcription/Translation/Synthesi s: b) RNA viruses: –“+” sense RNA acts as mRNA - viral proteins are made immediately in cytoplasm mediated by viral enzymes –“-” sense RNA (e.g. influenza) - lst makes a “+” sense RNA copy via viral enzyme
- 95. Viral Replication iv) Transcription/Translation/Synthesis: • Retroviridae (e.g. HIV) • Contain enzyme “Reverse transcriptase” • “+” sense Viral RNA cDNA integrated into host cell chromosome • mRNA (for viral proteins) and progeny virion RNA are synthesized from integrated viral DNA by host cell enzymes (RNA polymerases)
- 96. Viral Replication v) Synthesis: Protein synthesis - 2 types • structural • non-structural (enzymes for replication) Nucleic acid synthesis • new virus genome • most often by a virus - coded polymerase or replicase; with some DNA viruses a cell enzyme carries this out
- 97. Viral Replication vi) Assembly: may take place in cell nucleus, cytoplasm or (with most enveloped viruses) at the plasma membrane vii) Release: sudden rupture of cell gradual extrusion (budding) of enveloped viruses through the cell membrane may occur together with assembly
- 98. Enveloped Virus Entry via Fusion
- 99. Non-enveloped Virus Entry via Endocytosis
- 100. Outcome of Viral Infections Virus-host cell interaction may result in: 1. Cell death (lytic) - due to cytopathic effect of virus 2. Cell transformation - cell converted to malignant or cancerous cell 3. Latent infection (occult) - persistent infection in quiescent state which may reactive anytime to produce disease; continuous or intermittent shedding 4. Cell fusion to form multinucleated cells
- 101. Persistent Viral Infections 3 types of persistent viral infection (some overlap): 1. Chronic carrier - eg. Hepatitis B; results in chronic illness 2. Latent infection - eg. Herpesviridae; result in symptomatic or asymptomatic shedding 3. Slow virus infections - due to prolonged incubation period (eg. Measles virus and SSPE)
- 102. Host - Organism Relationship • Interaction between host and organism affecting the development and outcome of an infection includes: – Host’s primary physical barriers – Host’s immunologic ability to control and eliminate the invading organisms – Organism’s ability to evade, destruction/virulence – Ability of organism to spread in the body
- 103. Virulence of Viruses & Evasion of the Immune Response Poorly understood processes: Antigenic variation Some viruses encode receptors for various mediators of immunity (eg. IL1 & TNF) thus blocking their ability to interact with receptors on their intended targets Some viruses (eg. HIV) reduce expression of class I MHC proteins, thus reducing ability of cytotoxic T cells to kill the virus-infected cells Direct cell-to-cell propagation Attenuated viruses (eg. Vaccine strains)
- 104. Definitions Exposure: contact with a potentially infectious agent Infection: persistence on or within another living organism Disease: end product (damage) resulting from an infectious process Incubation: time from infection to development of symptoms / disease
- 105. Virus: Incubation Times Hours to 1-2 days: Respiratory viruses GI viruses 1 to 3 weeks: Measles/Mumps/Rubel la VZV, HSV Chlamydia Enteroviruses, Polio WNV Weeks to months: • Hepatitis viruses • HIV • EBV • Rabies Months to years: • Prions
- 108. Routes of Transmission Horizontal transmission: Direct contact (secretions, blood etc.) Respiratory (aerosol) Contaminated inanimate objects Insect vector (mosquitoes, ticks, etc.) Zoonoses Vertical transmission: Mother to fetus [Transplacental (Congenital), Perinatally]
- 109. Viruses - Transmission Can occur - with or without disease - during asymptomatic shedding - during incubation period Transmission results in primary infection disease; reactivation results in secondary disease
- 110. Viruses - Epidemiology mode of transmission age gender ethnic background / country of origin travel history occupation season underlying medical condition(s)
- 111. DEFINITIONS - VIRAL PROTEINS STRUCTURAL PROTEINS ALL PROTEINS IN A MATURE VIRION NON-STRUCTURAL PROTEINS VIRALLY CODED PROTEINS WHICH ARE NOT PACKAGED IN THE VIRION 111
- 112. EFFECTS ON HOST MAY INHIBIT HOST DNA, RNA OR PROTEIN SYNTHESIS DETAILS AND MECHANISM VARY 112
- 113. CYTOPATHIC EFFECT ANY DETECTABLE CHANGES IN THE HOST CELL MORPHOLOGICAL CHANGES 113
- 114. 114 Hockley et al. J Gen Virol 69:2455-2469 uninfected HIV infected HIV infected (at higher magnifcation)
- 115. CYTOPATHIC EFFECT ANY DETECTABLE CHANGES IN THE HOST CELL MORPHOLOGICAL CHANGES DEATH APOPTOSIS INDEFINITE GROWTH 115
- 116. 116
- 117. 117
- 118. tissue culture cells 118epithelial epithelioid fibroblastic slides from CDC
- 119. epithelial cells - adenovirus 119uninfected early infection late infection slides from CDC
- 120. epithelial cells - respiratory syncytial virus 120uninfected respiratory syncytial virus slides from CDC
- 121. fibroblastic cells - herpes simplex virus 121uninfected early infection late infection slides from CDC
- 122. fibroblastic cells - poliovirus 122uninfected early infection late infection slides from CDC
- 126. 126Diluted 10 fold Diluted 100 fold Diluted 1000 fold
- 128. SOME POINTS TO REMEMBER INFECTIVITY NOT EVERY RELEASED PARTICLE IS INFECTIOUS 128 • ASSAYS – detect every particle (e.g. electron microscope) – detect infectious particles only (e.g. plaque assay)
- 129. GLOSSARY 129