Viruses interact with host cells in ways that uniquely reveal a great deal about general aspects of molecular and cellular structure and function. Molecular and Cellular Biology of Viruses leads students on an exploration of viruses by supporting engaging and interactive learning. All the major classes of viruses are covered, with separate chapters for their replication and expression strategies, and chapters for mechanisms such as attachment that are independent of the virus genome type. Specific cases drawn from primary literature foster student engagement. End-of-chapter questions focus on analysis and interpretation with answers being given at the back of the book. Examples come from the most-studied and medically important viruses such as HIV, influenza, and poliovirus. Plant viruses and bacteriophages are also included. There are chapters on the overall effect of viral infection on the host cell. Coverage of the immune system is focused on the interplay between host defenses and viruses, with a separate chapter on medical applications such as anti-viral drugs and vaccine development. The final chapter is on virus diversity and evolution, incorporating contemporary insights from metagenomic research.
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CoverHalf TitleTitle PageCopyright PageDedicationContentsPrefaceAcknowledgmentsAuthor1. The Fundamentals of Molecular and Cellular Virology1.1 Molecular and cellular virology focuses on the molecular interactions that occur when a virus infects a host cell1.2 The discipline of virology can be traced historically to agricultural and medical science1.3 Basic research in virology is critical for molecular biology, both historically and today1.4 Viruses, whether understood as living or not, are the most abundant evolving entities known1.5 Viruses can be defined unambiguously by four traits1.6 Virions are infectious particles minimally made up of nucleic acids and proteins1.7 Viruses can be classified according to the ways they synthesize and use mRNA1.8 Viruses are propagated in the laboratory by mixing them with host cells1.9 Viral sequences are ubiquitous in animal genomes, including the human genomeEssential conceptsQuestionsFurther reading2. The Virus Replication Cycle2.1 Viruses reproduce through a lytic virus replication cycle2.2 Molecular events during each stage of the virus replication cycle2.3 The influenza virus is a model for replication of an animal virus2.4 The host surface is especially important for attachment, penetration, and uncoating2.5 Viral gene expression and genome replication take advantage of host transcription, translation, and replication features2.6 The host cytoskeleton and membranes are typically crucial during virus assembly2.7 Host-cell surfaces influence the mechanism of virus release2.8 Viruses can also cause long-term infections2.9 Herpesvirus is a model for latent infections2.10 Research in molecular and cellular virology often focuses on the molecular details of each stage of the replication cycleEssential conceptsQuestionsFurther reading3. Attachment, Penetration, and Uncoating3.1 Viruses enter the human body through one of six routes3.2 The likelihood of becoming HIV+ depends on the route of transmission and the amount of virus in the infected tissue3.3 Viruses are selective in their host range and tissue tropism3.4 The virion is a genome delivery device3.5 The genomic contents of a virion are irrelevant for attachment, penetration, and uncoating3.6 Animal viruses attach to specific cells and can spread to multiple tissues3.7 Noncovalent intermolecular forces are responsible for attaching to host cells3.8 Most animal virus receptors are glycoproteins3.9 Animal virus receptors can be identified through genetic, biochemical, and immunological approaches3.10 Animal virus receptors can be identified through molecular cloning3.11 Animal virus receptors can be identified through affinity chromatography3.12 Antibodies can be used to identify animal virus receptors3.13 Rhinovirus serves as a model for attachment by animal viruses lacking spikes3.14 Several independent lines of evidence indicate that ICAM-1 is the rhinovirus receptor3.15 Experiments using molecular genetics support the conclusion that ICAM-1 is the rhinovirus receptor3.16 Structural biology experiments support the conclusion that ICAM-1 is the rhinovirus receptor3.17 Bioinformatics comparisons support the conclusion that ICAM-1 is the rhinovirus receptor3.18 Influenza serves as a model for attachment by enveloped viruses3.19 The influenza HA spike protein binds to sialic acids3.20 The second stage of the virus replication cycle includes both penetration and uncoating and, if necessary, transport to the nucleus3.21 Viruses subvert the two major eukaryotic mechanisms for internalizing particles3.22 Many viruses subvert receptor-mediated endocytosis for penetration3.23 Herpesvirus penetrates the cell through phagocytosis3.24 Common methods for determining the mode of viral penetration include use of drugs and RNA interference3.25 The virion is a metastable particle primed for uncoating once irreversible attachment and penetration have occurred3.26 Picornaviruses are naked viruses that release their genomic contents through pore formation3.27 Some enveloped viruses use membrane fusion with the outside surface of the cell for penetration3.28 Vesicle fusion in neuroscience is a model for viral membrane fusion3.29 HIV provides a model of membrane fusion triggered by a cascade of protein–protein interactions3.30 Influenza provides a model for viral envelope fusion triggered by acidification of an endocytic vesicle3.31 The destination for the virus genome may be the cytoplasm or the nucleus3.32 Subversion of the cellular cytoskeleton is critical for uncoating3.33 Viruses that enter an intact nucleus must manipulate gated nuclear pores3.34 Viruses introduce their genomes into the nucleus in a variety of ways3.35 Adenovirus provides a model for uncoating that delivers the viral genome into the nucleus3.36 The unusual uncoating stages of reoviruses and poxviruses leave the virions partially intact in the cytoplasm3.37 Viruses that penetrate plant cells face plant-specific barriers to infection3.38 Plant viruses are often transmitted by biting arthropod vectorsEssential conceptsQuestionsFurther reading4. Gene Expression and Genome Replication in Model Bacteriophages4.1 Bacterial host cell transcription is catalyzed by a multisubunit machine that catalyzes initiation, elongation, and termination4.2 Bacterial host cell and bacteriophage mRNA are typically polycistronic4.3 Transcription and translation in bacterial host cells and bacteriophages are nearly simultaneous because of the proximity of ribosomes and chromosomes4.4 Bacterial translation initiation, elongation, and termination are controlled by translation factors4.5 Bacteriophages, like all viruses, encode structural and nonstructural proteins4.6 The T7 bacteriophage has naked, complex virions and a large double-stranded DNA genome4.7 Bacteriophage T7 encodes 55 proteins in genes that are physically grouped together by function4.8 Bacteriophage T7 proteins are expressed in three major waves4.9 The functions of bacteriophage proteins often correlate with the timing of their expression4.10 Bacteriophage T7 gene expression is highly regulated at the level of transcription initiation4.11 Bacterial host chromosome replication is regulated by the DnaA protein and occurs via a ? intermediate4.12 Many bacterial proteins are needed to catalyze chromosome replication4.13 Although many bacteriophages have linear dsDNA genomes, bacterial hosts cannot replicate the ends of linear DNA4.14 T7 bacteriophage genome replication is catalyzed by one of the simplest known replication machines4.15 The ? bacteriophage has naked, complex virions and a large double-stranded DNA genome4.16 Bacteriophage ? can cause lytic or long-term infections4.17 There are three waves of gene expression during lytic ? replication4.18 The ? control region is responsible for early gene expression because of its promoters and the Cro and N proteins it encodes4.19 The ? N antitermination protein controls the onset of delayed-early gene expression4.20 The ? Q antitermination protein and Cro repressor protein control the switch to late gene expression4.21 Bacteriophages T7 and ? both have three waves of gene expression but the molecular mechanisms controlling them differ4.22 Bacteriophage ? genome replication occurs in two stages, through two different intermediates4.23 Lambda genome replication requires phage proteins O and P and many subverted host proteins4.24 The abundance of host DnaA protein relative to the amount of phage DNA controls the switch to rolling-circle replication4.25 There are billions of other bacteriophages that regulate gene expression in various ways4.26 Some bacteriophages have ssDNA, dsDNA, or (+) ssRNA genomes4.27 The replication cycles of ssDNA bacteriophages always include formation of a double-stranded replicative form4.28 Bacteriophage ??174 is of historical importance4.29 Bacteriophage ??174 has extremely overlapping protein-coding sequences4.30 Bacteriophage ??174 proteins are expressed in different amounts4.31 A combination of mRNA levels and differential translation accounts for levels of bacteriophage ??174 protein expression4.32 Bacteriophage M13 genome replication is catalyzed by host proteins and occurs via a replicative form4.33 Bacteriophage MS2 is a (+) ssRNA virus that encodes four proteins4.34 Bacteriophage MS2 protein abundance is controlled by secondary structure in the genome4.35 Bacteriophage RdRp enzymes subvert abundant host proteins to create an efficient replicase complex4.36 Bacteriophage proteins are common laboratory toolsEssential conceptsQuestionsFurther reading5. Gene Expression and Genome Replication in the Positive-Strand RNA Viruses5.1 Class IV virus replication cycles have common gene expression and genome replication strategies5.2 Terminal features of eukaryotic mRNA are essential for translation5.3 Monopartite Class IV (+) strand RNA viruses express multiple proteins from a single genome5.4 Picornaviruses are models for the simplest (+) strand RNA viruses5.5 Class IV viruses such as poliovirus encode one or more polyproteins5.6 Class IV viruses such as poliovirus use proteolysis to release small proteins from viral polyproteins5.7 Translation of Class IV virus genomes occurs despite the lack of a 5′ cap5.8 Class IV virus genome replication occurs inside a virus replication compartment5.9 The picornavirus 3Dpol is an RdRp and synthesizes a protein-based primer5.10 Structural features of the viral genome are essential for replication of Class IV viral genomes5.11 Picornavirus genome replication occurs in four phases5.12 Flaviviruses are models for simple enveloped (+) strand RNA viruses5.13 The linear (+) strand RNA flavivirus genomes have unusual termini5.14 Enveloped HCV encodes 10 proteins including several with transmembrane segments5.15 Togaviruses are small enveloped viruses with replication cycles more complex than those of the flaviviruses5.16 Four different togavirus polyproteins are found inside infected cells5.17 Different molecular events predominate early and late during togavirus infection5.18 Translation of togavirus sgRNA requires use of the downstream hairpin loop5.19 Suppression of translation termination is necessary for production of the nonstructural p1234 Sindbis virus polyprotein5.20 Sindbis virus uses an unusual mechanism to encode the TF protein5.21 A programmed ?1 ribosome frameshift is needed to produce the togavirus TF protein5.22 The picornaviruses, flaviviruses, and togaviruses illustrate many common properties among (+) strand RNA viruses5.23 Coronaviruses have long (+) strand RNA genomes and novel mechanisms of gene expression and genome replication5.24 Coronaviruses have enveloped spherical virions and encode conserved and species-specific accessory proteins5.25 Coronaviruses express a nested set of sgRNAs with leader and TRS sequences5.26 Coronaviruses use a discontinuous mechanism for synthesis of replicative forms5.27 Most coronavirus sgRNA is translated into a single protein5.28 Coronaviruses use a leaky scanning mechanism to synthesize proteins from overlapping sequences5.29 Coronaviruses may proofread RNA during synthesis5.30 Plants can also be infected by Class IV RNA viruses5.31 Comparing Class IV viruses reveals common themes with variationsEssential conceptsQuestionsFurther reading6. Gene Expression and Genome Replication in the Negative-Strand RNA Viruses6.1 Study of two historically infamous Class V viruses, rabies and influenza, were instrumental in the development of molecular and cellular virology6.2 The mononegavirus replication cycle includes primary and secondary transcription catalyzed by the viral RdRp6.3 Rhabdoviruses have linear (?) RNA genomes and encode five proteins6.4 Rhabdoviruses produce five mRNAs with 5′ caps and polyadenylated 3′ tails through a start–stop mechanism6.5 Rhabdovirus genome replication occurs through the use of a complete antigenome cRNP as a template6.6 The paramyxoviruses are mononegaviruses that use RNA editing for gene expression6.7 Filoviruses are filamentous mononegaviruses that encode seven to nine proteins6.8 The filovirus VP30 protein, not found in other mononegaviruses, is required for transcription6.9 Influenza is an example of an orthomyxovirus6.10 Of the 17 influenza A proteins, 9 are found in the virion6.11 Orthomyxovirus nucleic acid synthesis occurs in the host cell nucleus, not in the cytoplasm6.12 The first step of transcription by influenza virus is cap snatching6.13 An influenza cRNP intermediate is used as the template for genome replication6.14 Arenavirus RNA genomes are ambisense6.15 Expression of the four arenavirus proteins reflects the ambisense nature of the genomeEssential conceptsQuestionsFurther reading7. Gene Expression and Genome Replication in the Double-Stranded RNA Viruses7.1 The rotavirus replication cycle includes primary transcription, genome replication, and secondary transcription inside partially intact capsids in the host cytoplasm7.2 Rotavirus A has a naked capsid with three protein layers enclosing 11 segments of dsRNA7.3 Rotavirus A encodes 13 proteins7.4 Synthesis of rotavirus nucleic acids occurs in a fenestrated double-layered particle7.5 Translation of rotavirus mRNA requires NSP3 and occurs in viroplasm formed by NSP2 and NSP57.6 Rotavirus genome replication precedes secondary transcriptionEssential conceptsQuestionsFurther reading8. Gene Expression and Genome Replication in the Double-Stranded DNA Viruses8.1 DNA viruses can cause productive lytic infections, cellular transformation, or latent infections8.2 Most Class I animal viruses rely on host transcription machinery for gene expression8.3 Eukaryotic transcription is affected by the state of the chromatin8.4 Eukaryotic capping, splicing, and polyadenylation occur co-transcriptionally8.5 Polyomaviruses are small DNA viruses with early and late gene expression8.6 The SV40 polyomavirus encodes seven proteins in only 5,243 bp of DNA8.7 The synthesis of mRNA in SV40 is controlled by the noncoding control region8.8 Late SV40 transcription is regulated by both host and viral proteins8.9 Most Baltimore Class I viruses including polyomaviruses manipulate the eukaryotic cell cycle8.10 Most Class I viruses prevent or delay cellular apoptosis8.11 SV40 forces the host cell to express S phase genes and uses large T antigen and host proteins for genome replication8.12 SV40 genome replication requires viral and host proteins to form active DNA replication forks8.13 The papillomavirus replication cycle is tied closely to the differentiation status of its host cell8.14 Human papillomaviruses encode about 13 proteins that are translated from polycistronic mRNA8.15 The long control region of HPV regulates papillomavirus transcription in which pre-mRNA is subjected to alternative splicing8.16 Leaky scanning, internal ribosome entry sites, and translation re-initiation lead to the expression of papillomavirus proteins from polycistronic mRNA8.17 DNA replication in papillomaviruses is linked to host cell differentiation status8.18 Papillomaviruses use early proteins to manipulate the host cell cycle and apoptosis8.19 Comparing the small DNA viruses reveals similar economy in coding capacity but different mechanisms for gene expression, manipulating the host cell cycle, and DNA replication8.20 Adenoviruses are large dsDNA viruses with three waves of gene expression8.21 Adenoviruses have large naked spherical capsids with prominent spikes and large linear dsDNA genomes8.22 Adenoviruses encode early, delayed-early, and late proteins8.23 The large E1A protein is important for regulating the adenovirus cascade of gene expression8.24 Splicing of pre-mRNA was first discovered through studying adenovirus gene expression8.25 Both host cells and adenovirus rely on alternative splicing to encode multiple proteins using the same DNA sequence8.26 Regulated alternative splicing of a late adenovirus transcript relies on cis-acting regulatory sequences, on the E4-ORF4 viral protein, and on host splicing machinery8.27 Adenovirus shuts off translation of host mRNA, while ensuring translation of its own late mRNAs through a ribosome-shunting mechanism8.28 DNA replication in adenovirus requires three viral proteins even though the genome is replicated in the host cell nucleus8.29 Herpesviruses have very large enveloped virions and large linear dsDNA genomes8.30 Lytic herpesvirus replication involves a cascade with several waves of gene expression8.31 Groups of herpes simplex virus 1 proteins have functions relating to the timing of their expression8.32 Waves of gene expression in herpesviruses are controlled by transcription activation and chromatin remodeling8.33 Herpesvirus genome replication results in concatamers8.34 Poxviruses are extremely large dsDNA viruses that replicate in the host cytoplasm8.35 Many vaccinia virus proteins are associated with the virion itself8.36 Vaccinia RNA polymerase transcribes genes in three waves using different transcription activators8.37 Vaccinia genome replication requires the unusual ends of the genome sequence8.38 The synthetic demands on the host cell make vaccinia a possible anticancer treatmentEssential conceptsQuestionsFurther reading9. Gene Expression and Genome Replication in the Single-Stranded DNA Viruses9.1 The ssDNA viruses express their genes and replicate their genomes in the nucleus9.2 Circoviruses are tiny ssDNA viruses with circular genomes9.3 Although their genomes are shorter than an average human gene, circoviruses encode at least four proteins9.4 Both host and viral proteins are needed for circovirus genome replication9.5 Parvoviruses are tiny ssDNA viruses with linear genomes having hairpins at both ends9.6 The model parvovirus MVM encodes six proteins using alternative splicing9.7 The model parvovirus MVM uses a rolling-hairpin mechanism for genome replicationEssential conceptsQuestionsFurther reading10. Gene Expression and Genome Replication in the Retroviruses and Hepadnaviruses10.1 Viral reverse transcriptases have polymerase and RNase H activity10.2 Retroviruses are enveloped and have RNA genomes yet express their proteins from dsDNA10.3 Reverse transcription occurs during transport of the retroviral nucleic acid to the nucleus, through a discontinuous mechanism10.4 Retroviral integrase inserts the viral cDNA into a chromosome, forming proviral DNA that can be transcribed by host Pol II10.5 All retroviruses express eight essential proteins, whereas some such as HIV encode species-specific accessory proteins10.6 The retroviral LTR sequences interact with host proteins to regulate transcription10.7 The compact retroviral genome is used economically to encode many proteins through the use of polyproteins, alternative splicing, and translation of polycistronic mRNA10.8 The HIV-1 accessory protein TAT is essential for viral gene expression10.9 The HIV-1 accessory protein Rev is essential for exporting some viral mRNA from the nucleus10.10 Retrovirus genome replication is accomplished by host Pol II10.11 HIV-1 is a candidate gene therapy vector for diseases that involve the immune cells normally targeted by HIV10.12 Hepadnaviruses are enveloped and have genomes containing both DNA and RNA in an unusual arrangement10.13 Hepadnaviruses use reverse transcription to amplify their genomes10.14 The cccDNA of HBV is not perfectly identical to the DNA in the infecting virion10.15 The tiny HBV genome encodes eight proteins through alternative splicing, overlapping coding sequences, and alternative start codons10.16 HBV genome replication relies upon an elaborate reverse transcriptase mechanismEssential conceptsQuestionsFurther reading11. Assembly, Release, and Maturation11.1 The last stages of the virus replication cycle are assembly, release, and maturation11.2 Unlike cells, viruses assemble from their constituent parts11.3 Virions more structurally complex than TMV also reproduce by assembly, not by division11.4 Typical sites of assembly in eukaryotic viruses include the cytoplasm, plasma membrane, and nucleus11.5 Eukaryotic virus assembly must take cellular protein localization into account11.6 Capsids and nucleocapsids associate with genomes using one of two general strategies11.7 Assembly of some viruses depends on DNA replication to provide the energy to fill the icosahedral heads11.8 Assembly of some viruses depends on a packaging motor to fill the icosahedral heads11.9 Negative RNA viruses provide a model for concerted nucleocapsid assembly11.10 To assemble, some viruses require assistance from proteins not found in the virion11.11 Viruses acquire envelopes through one of two pathways11.12 The helical vRNPs of influenza virus assemble first, followed by envelope acquisition at the plasma membrane11.13 Some viruses require maturation reactions during release in order to form infectious virions11.14 Assembly of HIV occurs at the plasma membrane11.15 Inhibition of HIV-1 maturation provides a classic example of structure–function research in medicine11.16 Release from bacterial cells usually occurs by lysis11.17 Release from animal cells can occur by lysis11.18 Release from animal cells can occur by budding11.19 Release from plant cells often occurs through biting arthropodsEssential conceptsQuestionsFurther reading12. Virus–Host Interactions during Lytic Growth12.1 All viruses subvert translation12.2 Bacteriophages subvert translation indirectly12.3 Animal viruses have many strategies to block translation of host mRNA12.4 Animal viruses cause structural changes in host cells referred to as cytopathic effects12.5 Viruses affect host cell apoptosis12.6 Some viruses delay apoptosis in order to complete their replication cycles before the host cell dies12.7 Some viruses subvert apoptosis in order to complete their replication cycles12.8 Viruses use the ubiquitin system to their advantage12.9 Viruses can block or subvert the cellular autophagy system12.10 Viruses subvert or co-opt the misfolded protein response triggered in the endoplasmic reticulum12.11 Viruses modify internal membranes in order to create virus replication compartmentsEssential conceptsQuestionsFurther reading13. Persistent Viral Infections13.1 Some bacteriophages are temperate and can persist as genomes integrated into their hosts’ chromosomes13.2 Bacteriophage ? serves as a model for latency13.3 The amount of stable CII protein in the cell determines whether the phage genome becomes a prophage13.4 Activation of PRE, PI, and PantiQ by CII results in lysogeny13.5 Stress triggers an exit from lysogeny13.6 Some lysogens provide their bacterial hosts with virulence genes13.7 Prophages affect the survival of their bacterial hosts13.8 Persistent infections in humans include those with ongoing lytic replication and latent infections13.9 Human immunodeficiency virus causes persistent infections13.10 Human herpesvirus 1 is a model for latent infections13.11 Oncogenic viruses cause cancer through persistent infections13.12 DNA viruses transform cells with oncoproteins that affect the cell cycle and apoptosis13.13 HPV oncoproteins E6 and E7 cause transformation13.14 HPV E6 and E7 overexpression occurs when the virus genome recombines with a host chromosome13.15 Merkel cell polyomavirus is also associated with human cancers13.16 Epstein–Barr virus is an oncogenic herpesvirus13.17 Latency-associated viral proteins are responsible for Epstein–Barr virus-induced oncogenesis13.18 The Kaposi’s sarcoma herpesvirus also causes persistent oncogenic infections13.19 Hepatocellular carcinoma is caused by persistent lytic viral infections13.20 Retroviruses have two mechanisms by which they can cause cancer13.21 Viral oncoproteins can be used to immortalize primary cell cultures13.22 The human virome is largely uncharacterized but likely has effects on human physiologyEssential conceptsQuestionsFurther reading14. Viral Evasion of Innate Host Defenses14.1 Restriction enzymes are a component of innate immunity to bacteriophages14.2 Bacteriophages have counterdefenses against restriction-modification systems14.3 Human innate immune defenses operate on many levels14.4 The human innate immune system is triggered by pattern recognition14.5 Innate immune responses include cytokine secretion14.6 Interferon causes the antiviral state14.7 Some viruses can evade the interferon response14.8 Neutrophils are active during an innate immune response against viruses14.9 Viruses manipulate immune system communication to evade the net response14.10 Inflammation is the hallmark of an innate immune response14.11 In order to be recognized as healthy, all cells present endogenous antigens in MHC-I molecules14.12 Cells infected by viruses produce and display viral antigens in MHC-I14.13 Viruses have strategies to evade MHC-I presentation of viral antigens14.14 Natural killer cells attack cells with reduced MHC-I display14.15 The complement system targets enveloped viruses and cells infected by them14.16 Some viruses can evade the complement system14.17 Viral evasion strategies depend on the coding capacity of the virus14.18 In vertebrates, if an innate immune reaction does not clear an infection, adaptive immunity comes into playEssential conceptsQuestionsFurther reading15. Viral Evasion of Adaptive Host Defenses15.1 CRISPR-Cas is an adaptive immune response found in bacteria15.2 Some bacteriophages can evade or subvert the CRISPR-Cas system15.3 The human adaptive immune response includes cell-mediated and humoral immunity15.4 The human adaptive immune response has specificity because it responds to epitopes15.5 Professional antigen-presenting cells degrade exogenous antigens and display epitopes in MHC-II molecules15.6 Some viruses evade MHC-II presentation15.7 Lymphocytes that control viral infections have many properties in common15.8 CD4+ helper T lymphocytes interact with viral epitopes displayed in MHC-II molecules15.9 Antibodies are soluble B-cell receptors that bind to extracellular antigens such as virions15.10 During an antiviral response, B cells differentiate to produce higher-affinity antibodies15.11 Viruses have strategies to evade or subvert the antibody response15.12 CD8+ cytotoxic T lymphocytes are crucial for controlling viral infections15.13 Some viruses can evade the CTL response15.14 Viruses that cause persistent infections evade immune clearance for a long period of time15.15 The immune response to influenza serves is a comprehensive model for antiviral immune responses in general15.16 Influenza provides a model for how a lytic virus evades both innate and adaptive immunity long enough to replicateEssential conceptsQuestionsFurther reading16. Medical Applications of Molecular and Cellular Virology16.1 Vaccines are critical components of an effective public health system16.2 Attenuated vaccines are highly immunogenic because they can still replicate16.3 Inactivated vaccines are composed of nonreplicating virions16.4 Subunit vaccines are composed of selected antigenic proteins16.5 Although seasonal influenza vaccines are useful, a universal flu vaccine is highly sought after16.6 Preventative HIV vaccines are in development16.7 Extreme antigenic variation is a problem for developing an HIV vaccine16.8 An effective HIV vaccine may require stimulating a strong CTL response16.9 Antiviral drugs target proteins unique to viruses and essential for their replication cycle16.10 Many antiviral drugs are nucleoside or nucleotide structural analogs that target the active site of viral polymerases16.11 Drugs to treat influenza target the uncoating and release stages of viral replication16.12 Drugs to treat hepatitis C virus target the viral polymerase16.13 Drugs to treat HIV target many stages of the virus replication cycle16.14 Viral evolution occurs in response to selective pressure from antiviral drugs16.15 It might be possible to develop bacteriophage therapy to treat people with antibiotic-resistant bacterial infections16.16 Engineered viruses could in principle be used for gene therapy to treat cancer and other conditions16.17 Gene therapy and oncolytic virus treatments currently in use16.18 Therapeutic applications of CRISPR-Cas technologyEssential conceptsQuestionsFurther reading17. Viral Diversity, Origins, and Evolution17.1 The viral world is extremely diverse17.2 Satellite viruses and nucleic acids require co-infection with a virus to spread17.3 Viroids are infectious RNA molecules found in plants17.4 Transposons and introns are subviral entities17.5 Viruses have ancient origins17.6 Viral hallmark proteins can be used to trace evolutionary history17.7 Metagenomics will revolutionize evolutionary understanding of viruses17.8 Viral genetic diversity arises through mutation and recombination17.9 Genetic diversity among influenza A viruses arises through mutation and recombination17.10 Influenza A spike proteins are particularly diverse17.11 Variations among influenza A viruses reflects genetic drift and natural selection17.12 Pandemic influenza A strains have arisen through recombination17.13 New pandemic influenza A strains may be able to arise through mutation17.14 Selective pressures and constraints influence viral evolution17.15 Some viruses and hosts coevolve17.16 Medically dangerous emerging viruses are zoonotic17.17 HIV exhibits high levels of genetic diversity and transferred from apes to humans on four occasions17.18 HIV-1 has molecular features that reflect adaptation to humans17.19 Viruses and subviral entities are common in the human genome17.20 Viruses and subviral entities have strongly affected the evolution of organisms including humans17.21 Virology unites the biosphereEssential conceptsQuestionsFurther reading18. Glossary19. AnswersIndex