Viruses on the Biological Spectrum Viruses can infect

Viruses on the Biological Spectrum Viruses can infect every type of cell: • Bacteria • Algae • Fungi • Protozoa • Plants • Animals Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 1

What is the Nature of Viruses? • Are they organisms? Are they alive? • What role did viruses play in the evolution of life? • What are their distinctive characteristics? • How can a particle so small, simple, and seemingly insignificant be capable of causing disease and death? • What is the connection between viruses and cancer? • What role did viruses play in the development of all other organisms? Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 2

Unique Properties of Viruses Infectious particles • Rather than organisms Active or inactive • Rather than alive or dead Obligate intracellular parasites: • Cannot multiply unless they invade a specific host cell • Must instruct the genetic and metabolic machinery of the host cell to make and release new viruses Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 3

Properties of Viruses • Are not cells • Are obligate intracellular parasites of bacteria, protozoa, fungi, algae, plants, and animals • Do not independently fulfill the characteristics of life • Are inactive macromolecules outside the host cell and active only inside host cells • Have basic structure of protein shell (capsid) surrounding nucleic acid core • Are ubiquitous in nature and have had major impact on development of biological life • Are ultramicroscopic in size, ranging from 20 nm to 1000 nm (diameter) • Can have either DNA or RNA but not both • Can have double-stranded DNA, single-stranded RNA, or double-stranded RNA • Carry molecules on surface that determine specificity for attachment to host cell • Multiply by taking control of host cell’s genetic material and regulating the synthesis and assembly of new viruses • Lack enzymes for most metabolic processes • Lack machinery for synthesizing proteins Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 4

Viral Size Range Ultramicroscopic size: Smaller than the average bacterium Electron microscopes are required to detect them • Parvoviruses: 0. 02 μm in diameter • Mimiviruses: 450 nm in length —larger than some small bacteria • Cylindrical viruses: 0. 8 μm long, but 0. 015 μm in diameter Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 5

Methods of Viewing Viruses Jump to image long description (a) CDC; (b) CDC/Frederick A. Murphy; (c) © A. B. Dowsette/Science Source Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 6

Viruses Bear no Resemblance to Cells Lack protein-synthesizing machinery Need only those parts required to invade and control a host cell: • External coating • Core containing nucleic acids © Omnikron/Science Source Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 7

Viral Components Capsid: • Shell surrounds the nucleic acid • Nucleocapsid: capsid and nucleic acid together Envelope: • Not found in all viruses • Usually a modified piece of the host cell membrane Naked viruses: • Consist only of a nucleocapsid Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 8

Viral Components Spikes: • Found on both naked and enveloped viruses • Project from either the nucleocapsid or envelope • Allow viruses to dock with their host cells Virion: • Fully formed virus able to establish infection in a host Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 9

Generalized Structure of Viruses Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 10

The Viral Capsid: The Protective Outer Shell Capsomeres: • Identical protein subunits that spontaneously self assemble to form the capsid Helical capsid: • Rod-shaped capsomeres that form a continuous helix around the nucleic acid Icosahedral capsid: • Three-dimensional, 20 -sided figure with 12 evenly spaced corners Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 11

Helical Nucleocapsids (b) © Science Source; (d) CDC/Cynthia Goldsmith Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 12

Icosahedral Capsids (a 1) CDC/Dr. Erskine Palmar; (a 2) © Dr Linda Stannard, Uct/Science Source; (b) © Eye of Science/Science Source © Dr. Linda M. Stannard, University of Cape Town/Science Source Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 13

The Viral Capsid Complex capsids: • Found in bacteriophage, the viruses that infect bacteria • Have multiple types of proteins (a) © Ami Images/Science Source • Take shapes that are not symmetrical Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 14

Nonenveloped and Enveloped Viruses (a) © BSIP/Universal Images Group/Getty Images; (b) © Kathy Park Talaro Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 15

The Viral Envelope Composed of the membrane system of the host • Cell membrane or nuclear membrane • Regular membrane proteins are replaced with viral proteins • Spikes: protruding glycoproteins essential for attachment to the host cell Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 16

Nucleic Acids: At the Core of a Virus Genome: the full complement of DNA and RNA carried by a cell Viruses contain either DNA or RNA but not both • The number of viral genes is small compared to that of a cell • Possess only the genes necessary to invade host cells and redirect their activity Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 17

Nucleic Acids Positive-sense RNA: • Single-stranded RNA genomes ready for immediate translation into proteins Negative-sense RNA: • RNA genomes that need to be converted into the proper form to be made into proteins Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 18

Viral Nucleic Acid Table 6. 2 Viral Nucleic Acid Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 19

Other Substances in the Virus Particle Enzymes for specific operations within the host cell: • Polymerases: synthesize DNA and RNA • Replicases: copy RNA • Reverse transcriptase: synthesizes DNA from RNA Substances from the host cell: • Arenaviruses pack along host ribosomes • Retroviruses “borrow” the host’s t. RNA molecules Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 20

Classification of Viruses Informal classification system: Virus families: • Animal, plant, or bacterial viruses • DNA or RNA viruses • Helical or icosahedral Virus genera: • Suffix –viridae • Suffix –virus Criteria of a formal classification system: • Structure • Chemical composition • Similarities in genetic makeup Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 21

Important Human Virus Families, Genera, Common Names, and Types of Diseases DNA Viruses Genus of Virus Common Name of Genus Members Variola and vaccinia Name of Disease Poxviridae Orthopoxvirus Herpesviridae Simplexvirus Fever blister, cold sores Varicellovirus Herpes simplex type 1 virus (HSV-1) Herpes simplex type 2 virus (HSV-2) Varicella zoster virus (VZV) Herpesviridae Simplexvirus Herpesviridae Cytomegalovirus Human cytomegalovirus (CMV) CMV infections Adenoviridae Mastadenovirus Human adenoviruses Adenovirus infection Papovaviridae Papillomavirus Human papillomavirus (HPV) Several types of warts Papovaviridae Polyomavirus JC virus (JCV) Hepadnaviridae Orthohepadnavirus Parvoviridae Erythrovirus Hepatitis B virus (HBV or Dane particle) Parvovirus B 19 Progressive multifocal leukoencephalopathy (PML) Serum hepatitis Smallpox, cowpox Genital herpes Chickenpox, shingles Erythema infectiosum Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 22

Important Human Virus Families, Genera, Common Names, and Types of Diseases RNA Viruses Common Name of Genus Members Poliovirus Name of Disease Picornaviridae Genus of Virus Enterovirus Picornaviridae Enterovirus Coxsackievirus Hand-foot-mouth disease Picornaviridae Hepatovirus Hepatitis A virus (HAV) Short-term hepatitis Picornaviridae Rhinovirus Human rhinovirus Common cold, bronchitis Caliciviridae Norovirus Norwalk virus Togaviridae Alphavirus Eastern equine encephalitis virus Viral diarrhea, Norwalk virus syndrome Eastern equine encephalitis (EEE) Togaviridae Alphavirus Western equine encephalitis (WEE) Togaviridae Alphavirus St. Louis encephalitis Togaviridae Rubivirus Rubella (German measles) Flaviviridae Flavivirus Dengue fever Flaviviridae Flavivirus West Nile fever Flaviviridae Flavivirus Yellow fever Poliomyelitis Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 23

Important Human Virus Families, Genera, Common Names, and Types of Diseases RNA Viruses Genus of Virus Common Name of Genus Members Name of Disease Coronaviridae Coronavirus Infectious bronchitis virus (IBV) Bronchitis Coronaviridae Coronavirus Coronaviridae Betacoronavirus Ebolavirus Marburgvirus Orthomyxoviridae Influenza A virus Enteric corona virus SARS virus Coronavirus enteritis Severe acute respiratory syndrome Ebola fever Filoviridae Ebola, Marburg virus Influenza or “flu” Paramyxoviridae Influenza virus, type A (Asian, Hong Kong, and swine influenza viruses) Parainfluenza virus, types 1– 5 Mumps virus Mumps Measles virus Measles Paramyxoviridae Respirovirus Rubulavirus Morbillivirus Paramyxoviridae Pneumovirus Respiratory syncytial virus (RSV) Common cold syndrome Rhabdoviridae Lyssavirus Rabies Paramyxoviridae Parainfluenza Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 24

Important Human Virus Families, Genera, Common Names, and Types of Diseases RNA Viruses Genus of Virus Name of Disease Orthobunyavirus Common Name of Genus Members Bunyamwera viruses Bunyaviridae Hantavirus Sin Nombre virus Respiratory distress syndrome Bunyaviridae Phlebovirus Rift Valley fever Bunyaviridae Nairovirus Reoviridae Coltivirus Crimean–Congo hemorrhagic fever virus (CCHF) Colorado tick fever virus Crimean–Congo hemorrhagic fever Colorado tick fever Reoviridae Rotavirus Human rotavirus Rotavirus gastroenteritis Retroviridae Deltaretrovirus T-cell leukemia Retroviridae Lentivirus Arenaviridae Arenavirus Human T-lymphotrophic virus 1 (HTLV-1) HIV (human immunodeficiency viruses 1 and 2) Lassa virus California encephalitis Acquired immunodeficiency syndrome (AIDS) Lassa fever Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 25

Multiplication Cycles in Animal Viruses General phases in the life cycle of animal viruses: • • • Adsorption Penetration Uncoating Synthesis Assembly Release from the host cell Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 26

General Features in the Multiplication Cycle of RNA Animal Viruses Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 27

General Features in the Multiplication Cycle of DNA Animal Viruses Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 28

Adsorption Invasion begins when the virus encounters a susceptible host and adsorbs specifically to receptor sites on the cell membrane • Adsorb: to attach (like a virus) • Absorb: to soak in (like a paper towel) Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 29

Host Range • A virus can invade its host cell only through making an exact fit with a specific host molecule • Restricted host range: hepatitis B only infects liver cells of humans • Moderately restrictive host range: poliovirus infects intestinal and nerve cells of primates • Broad host range: rabies virus infects various cells of all mammals Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 30

Penetration and Uncoating of Animal Viruses • Endocytosis: entire virus is engulfed by the cell and enclosed in a vacuole or vesicle • Uncoating: enzymes in the vacuole dissolve the envelope and capsid, releasing the virus into the cytoplasm Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 31

Synthesis: Replication and Protein Production Viral nucleic acid takes control over the host’s synthetic and metabolic machinery • Mechanism varies depending on whether the virus is a DNA or RNA virus • RNA viruses replicate in the cytoplasm • DNA viruses replicate in the nucleus Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 32

Nucleus of a Eukaryotic Cell, Containing Hundreds of Adenovirus Virions Courtesy Dr. Harold C. Smith, Department of Biochemistry and Biophysics, RNA Center & Cancer Center, University of Rochester Medical Center, Rochester, NY Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 33

Release of Mature Viruses Enveloped viruses are liberated by budding or exocytosis: • Nucleocapsid binds to the membrane • A small pouch is formed • Pinching off of the pouch releases the virus with its envelope • Viruses are shed gradually without destruction of the cell (b) © Chris Bjornberg/Science Source Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 34

Damage to the Host Cell Cytopathic Effects (CPEs): • Virus-induced damage to the cell that alters its microscopic appearance • Cells can become disoriented, undergo major changes in shape or size, or develop intracellular damage • Inclusion bodies: compacted masses of viruses or damaged cell organelles in the nucleus or cytoplasm • Syncytia (singular, syncytium): fusion of multiple host cells into single large cells containing multiple nuclei Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 35

Cytopathic Effects (a) © Dr. Diana Hardie, UCT/Science Source; (b) Courtesy Massimo Battaglia, INe. MM CNR, Rome Italty Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 36

Cytopathic Changes in Selected Virus-Infected Animal Cells Virus Response in Animal Cell Smallpox virus Cells round up; inclusions appear in cytoplasm Herpes simplex Cells fuse to form multinucleated syncytia; nuclear inclusions Adenovirus Clumping of cells; nuclear inclusions Poliovirus Cell lysis; no inclusions Reovirus Cell enlargement; vacuoles and inclusions in cytoplasm Influenza virus Cells round up; no inclusions Rabies virus No change in cell shape; cytoplasmic inclusions (Negri bodies) Measles virus Syncytia form (multinucleate) Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 37

Persistent Infections A carrier relationship that develops in some cells • Cell harbors the virus and is not immediately lysed • Provirus: viral DNA incorporated into the DNA of the host • Chronic latent state: periodic activation after a period of viral inactivity Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 38

Viruses and Cancer Oncogenic viruses: • Experts estimate that up to 13% of human cancers are caused by viruses Transformation: • Virus carries genes that directly cause cancer • Virus produces proteins that induce a loss of growth regulation in the cell Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 39

Viruses That Infect Bacteria Bacteriophage: • Discovered in 1915 by Frederick Twort and Felix d’Herelle • Parasitize every known bacterial species • Often make the bacteria they infect more pathogenic for humans Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 40

Bacteriophage “T-even” bacteriophage infect Escherichia coli • T-2 and T-4 • Most widely studied bacteriophage • Go through similar stages as animal viruses Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 41

Events in the Lytic Cycle of T-even Bacteriophages Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 42

Weakened Bacterial Cell, Crowded with Viruses © Lee D. Simon/Science Source Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 43

Bacteriophage Life Cycle • Lytic phase or lytic cycle: life cycle of bacteriophage that ends in destruction of the bacterial cell • Lysogenic cycle: bacteriophage becomes incorporated into the host cell DNA Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 44

Comparison of Bacteriophage and Animal Virus Multiplication Bacteriophage Animal Virus Penetration Precise attachment of special tail fibers to cell wall Injection of nucleic acid through cell wall; no uncoating of nucleic acid Synthesis and assembly Occurs in cytoplasm Attachment of capsid or envelope to cell surface receptors Whole virus is engulfed and uncoated, or virus surface fuses with cell membrane; nucleic acid is released Occurs in cytoplasm and nucleus Synthesis and assembly Cessation of host synthesis Synthesis and assembly Viral DNA or RNA is replicated and begins to function Viral components synthesized Viral persistence Lysogeny Latency, chronic infection, cancer Release from host cell Cell lyses when viral enzymes weaken it Immediate or delayed Some cells lyse; enveloped viruses bud off host cell membrane Immediate or delayed Adsorption Cell destruction Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 45

Techniques in Cultivating and Identifying Animal Viruses In vivo methods: viral cultivation in lab animals or embryonic bird tissues In vitro methods: viral cultivation in cell or tissue culture Primary Purposes of Viral Cultivation: • Isolate and identify viruses in clinical specimens • Prepare viruses for vaccines • Do detailed research on viral structure, multiplication cycles, genetics, and effects on host cells Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 46

Using Live Animal Inoculation Specially bred strains of animals used for animal cultivation of viruses: • • • White mice Rats Hamsters Guinea pigs Rabbits Injection sites for viral exposure: • • • Brain Blood Muscle Body cavity Skin Footpads Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 47

Using Bird Embryos Benefits of using bird embryos: • Embryonic development occurs in a protective shell • Intact and self-supporting unit with its own sterile environment and nourishment • Furnishes several embryonic tissues that support viral multiplication Courtesy Ted Heald, State of lowa Hygienic Laboratory Jump to image long description Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 48

Using Cell (Tissue) Culture Techniques Cell culture or tissue culture: in vitro virus cultivation systems • A simple and effective way to grow populations of isolated animal cells in culture dishes • Most viruses are propagated through cell culture • Much of a virologist’s work involves developing and maintaining cultures Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 49

Other Noncellular Infectious Agents (1) Spongiform encephalopathies: • Implicated in chronic, persistent disease in humans and animals • Brain tissue removed from affected animals resembles a sponge Prions: • Common feature of spongiform encephalopathies • Distinct protein fibrils deposited in brain tissue of affected animals Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 50

Other Noncellular Infectious Agents (2) Creutzfeldt-Jakob Disease (CJD): • • Afflicts the central nervous system of humans Causes gradual degeneration and death Transmissible by an unknown mechanism Several animals are victims of similar diseases: • Scrapie: sheep, mink elk • Bovine spongiform encephalopathy: cows Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 51

Other Noncellular Infectious Agents (3) Prion infection: • Exact mode of infection is unknown • Protein composition of prions has revolutionized ideas of what can constitute an infectious agent • Questions about how prions replicate given that they have no nucleic acid Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 52

Viruses and Human Health Impossible to measure the number of viral infections worldwide Most common cause of acute infections that do not result in hospitalization: • Colds, chickenpox, influenza, herpes, warts Viral infections that only occur in certain regions: • Dengue fever, Rift Valley fever, Yellow fever Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 53

Viruses and Human Health Some have high mortality rates: • Rabies • Ebola Other viral infections lead to long-term disability: • Polio • Neonatal rubella Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 54

Viruses and Human Health Viruses mutate at a rapid rate Difficult to design therapies against viruses Scientists focus on developing vaccines against viruses since so few antiviral drugs are available and antibiotics are ineffective Interferon (IFN): • Naturally occurring human cell product • Used with some success in preventing and treating viral infections Copyright © 2018 Mc. Graw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of Mc. Graw-Hill Education. 55