Chapter 23: Introduction to Viruses

1
Chapter 23 Introduction to Viruses

• General characteristics of Viruses
• Obligate intracellular parasites of living cells
  require living cells to replicate host cell is
  always harmed
• Viruses are not living, not cells are infectious
  infect every known cell type
• Heterogeneous group of agents that vary in size,
  morphology, complexity and host range
• Consist of a GENOME, either RNA or DNA, but not
  both complex chemical entities possessing a
  complete genetic mechanism
• Genome is surrounded by a protein coat CAPSID
• CAPSOMERE repeating structural units of capsid
• Structure consisting of genome capsid
  NUCLEOCAPSID
• Additional feature in many viruses ENVELOP
  composed of protein-containing lipid-bilayer
  (glycoprotein and lipid)
• Encloses the capsid
• Derived from the nuclear membrane of the host
• Peplomere glycoprotein subunit of envelope
  project outward - spikelike
• Further distinguishes viral groups
• VIRION complete virus particle nucleic acid
  genome, surrounded by capsid
• Pathogenicity of viruses dependent upon variety
  of structural functional characteristcs.

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Introduction to Viruses

• General characteristics of Viruses
• Viruses are ASSEMBLED they do NOT replicate by a
  division process
• Products are made put together (virion)
  reproduction by assembly not by binary fission.
• Viruses are genetic parasites
• Dependent upon the genetic mechanisms of host
  cell to reproduce them
• Lack enzymes for metabolic processes cannot make
  ATP (E) independently from host cell
• Virus components are synthesized by the host
  cell, NOT the virus
• Viruses must encode for any required processes
  not provided or synthesized by host cell viral
  components must self-assemble
• Viral synthesis assembly usually cause cell
  death or leave the cell metabolically
  dysfunctional
• Viruses cause cell death IS is compromised ? 2
  infections w/ bacteria ? (usu. Normal Flora)
• Viruses are cell or tissue specific display
  Trophism
• Each virus w/ its own type of host cell

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Introduction to Viruses

• General Characteristics of Viruses
• Untramicroscopic size ranging form 20 nm 450 nm
  gt very small much smaller than bacteria
• Filterable agents easily separated form bacteria
• Simplest viruses consist of a genome of DNA or
  RNA packaged in a protective protein shell, and a
  membrane in some viruses
• Have to enter, establish and replicate in the
  host thus, viruses are INFECTIOUS or cause
  infections
• Viruses are transmissible from person-to-person
• Viral infected cell will die (quickly or slowly)
• T-cell response kills the viral-infected cells

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Introduction to Viruses

• Characteristics used to define Viruses
• Type structure of viral nucleic acid
• ssDNA or dsDNA, linear or circular
• ssRNA of () sense gt mRNA form
• ssRNA of (-) sense gt antimessenger form that is
  complementary to messenger form
• dsRNA (/-) sense gt some virurses
• Ambiense genome
• Regions in genome are of () sense and (-) sense,
  attached end-to-end
• Mechanism used in its replication or means of
  replication
• Type of symmetry of virus capsid
• Helical
• Icosahedral
• Enveloped vs. Nonenveloped
• Note Both the capsid (of the nucleocapsid) the
  envelope (when present) contribute to the
  antigenticity of the virus
• Abs made in response to virus capsid proteins
  Ags expressed on viral envelops (when present)
  attract cytotoxic T-cells IS responds better to
  enveloped viruses

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Introduction to Viruses

• Summary of Virus Structure
• Virion nucleic acid (DNA or RNA) surrounded by
  protein coat.
• Envelope derived form host cell membrane lipid
  bilayer composed of lipid, protein and
  glycoproteins.
• Peplomeres spike-like projections of virus
  specific glycoproteins incorporated in the
  envelope involved in attachment of virus to cell
  receptor on the membrane of host cell.
• Capsid surrounds the viral genome composed of
  repeating units capsomeres protects the genome
  during transmission from one host cell to
  another involved in interaction between virus
  host cell during attachment step of replication
  process
• Capsomeres repeating unites that compose the
  capsid, which surrounds the virus genome
  arranged in either helical of icosahedral
  symmetry
• Nucleocapsid or Naked Capsid Virus DNA or RNA
  structural proteins w/ or w/out nucleic acid
  binding proteins
• Enveloped Viruses Nucleocapsid Glycoproteins
  Membrane Phspholipids

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Properties of Naked Virions (Nucleocapsid)

• Remains stable infectious in presence of
  environmental extremes
• Temperature
• Acids (extremes in pH)
• Proteases
• Detergents
• drying
• Released from host cell by lysis there is no
  envelope
• Epidemiological significance
• Can be transmitted easily
• Can dry retain infectivity
• Can survive the adverse conditions of the gut
• Can be resistant to antimicrobial effect of
  detergents sewage treatment processes
• Ab against capsid protein may be sufficient for
  protection

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Properties of Enveloped Virions

• Do NOT tolerate environmental conditions well
  are destroyed or inactivated in presence of
  environmental variables
• Acids (extremes in pH)
• Detergents
• Drying
• heat
• Modifies the host cell membrane thru addition of
  viral specific Ags or glycoproteins
• Are released by budding from host cell or by
  lysis (only few enveloped viruses)
• Epidemiological significance
• Must remain wet to be active infectious
• Cannot survive the harsh environment of GIT
• Does not need to kill the host cell to spread or
  be released
• Requires both humoral cell-mediated immunity
  for protection control
• Elicits hypersensitivity inflammation to cause
  immunopathogenesis

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Classification of Viruses

• Nucleic Acid type either DNA or RNA
• Presence or absence of Envelope
• Cell Trophism preference or affinity of virus
  to infect a particular cell type
• Ex. Hepatitis virus has an affinity for
  hepatocytes (liver cells)
• Different classification for RNA viruses
• Strand type () RNA and (-) RNA strand-sense
  based on direction of phosphate groups
• Presence or absence of envelope
• Cell trophism

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Families DNA Viruses

• Poxiviridae
• Herpesviridae
• Adenoviridae
• Hepadenoviridae
• Papovaviridae
• Parvoviridae

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Families of RNA Viruses

• Paramyxoviridae
• Orthomyxoviridiae
• Coronaviridae
• Arenaviridae
• Rhabdoviridae
• Filvoviridae
• Bunyviridae
• Retroviridae
• Reoviridae
• Picornaviridiae
• Togaviridae
• Flaviviridae
• Calciviridae
• Delta

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Viral Replication

• The ONE-Step Growth Curve (fig 23.7 p. 236)
• Representation of the overall ?, w/ time, in the
  amount of infectious virus in a single cell that
  has been infected by a single virus particle
• 2 components
• Eclipse period
• Period immediately following attachment of virus
  to host cell gt disappearance of ability to
  infect other cells
• Period of time between initial viral entry and
  dissassembly of parental virus ? assembly of 1st
  progeny virion
• Period of active synthesis of viral components
• 1-20 hours for most human viruses
• Exponential growth
• Exponential ? in of progeny cells produced w/in
  the infected host cell over a period of time,
  then plateau phase
• Plateau NO additional increase in virus yield
• Maximum yield/cell characteristic of each
  virus-cell system
• Reflects balance between rate _at_ which virus
  components continue to be synthesized assembled
  into virions, and rate _at_ which cells loses
  synthetic capacity structural integrity
• 8-72 hours, yielding 100-10,000
  virions/infected host cell

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The Virus Cycle

• Adsorption virus attaches to a permissive cell
  via a virus-specific receptor on the cell surface
• Binding of virion to host cell receptor (protein
  or CHO)
• Ability to adsorb determines host/tissue range of
  the virus
• Specific binding b/t virus capsid/envelope (Viral
  Attachment Proteins VAPs) and host receptor
• Prevention of this step BEST way to prevent
  entire virus cycle!
• Penetration or entry into the cell
• Nonenveloped viruses enter by receptor-mediated
  endocytosis or viropexis (direct penetration by
  some non-enveloped viruses)
• Endocytosis pinocytosis or engulfment of
  complete virion
• Viropexis gt For very SMALL viruses Hydrophobic
  component of capsid forces the virus thru host
  cell membrane
• Enveloped viruses enter by fusing the envelope w/
  the host cell membrane, and then deliver
  nucleocapsid or genome directly into the host
  cell cytoplasm released to area where
  replicated
• Virus merges or dissolves into the host membrane
  or endosome
• Mechanism governed by pH
• Neutral pH fusion w/ cell membrane
• Acid pH fusion w/ endosome

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The Virus Cycle

• Uncoating releases the nucleic acid into the
  cell removal of the nucleocapsid
• Virus-based enzyme carried in virion removes
  the capsid
• Cell-based enzymes or structures w/in host cells
  remove the capsid
• In general
• DNA viruses uncoated upon entry into host cell
  nucleus
• RNA viruses uncoated upon entry into cytoplasm
• 2 strategies
• Nucleocapsid remain in the cytoplasm genome is
  expressed while in association w/ nucleocapsid
  protein
• Capsid is removed to free the genome may remain
  in cytoplasm or be transported to nucleus before
  gene expression is initiated

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The Virus Cycle

• Replication of viral genome different
  strategies, depending upon the nature of the
  genome (DNA or RNA)
• Synthesis of viral proteins DNA and RNA viruses
  have different strategies
• Morphogenesis (Maturation) assembly of progeny
  virions in the cytoplasm or in the nucleus of
  infected cells
• Depends on the virus and cell involved
• Release progeny virions (both DNA RNA viruses)
  are released from infected cells by host cell
  lysis or by the process of budding from the host
  cell membrane, thus acquiring the envelop from
  the host.
• Budding from host cell membrane, but also ER
  and Nuclear membrane slow process host cell
  remains for 3wks, but is metabolically
  deficient, then dies
• Lysis host cell dies for non-enveloped viruses
• Note viruses that bud or acquire their membrane
  in cytoplasm remain cell-associated and are
  released by exocytosis or cell lysis

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Assembly of Nucleocapsids

• Generally takes place in host cell compartment
  where viral nucleic acid replication occurs
• Cytoplasm for RNA viruses
• Nucleus for DNA viruses
• Capsid proteins transported for cytoplasm to
  nucleus
• Self-assembly of capsid components w/ nucleic
  acid nucleocapsid

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Assembly contd

• Naked virions
• Unenveloped viruses
• Virion is complete w/ assembly of nucleocapsid
• Enveloped virions
• Virus-specific glycoproteins are synthesized
  transported to host cell membrane, where they
  insert
• Viral antigentic specificity is established on
  the host cell membrane
• Budding process
• Nucleocapsid is directed to host cell membrane
  enveloped
• Host cell membrane provides the viral envelop by
  this outward ballooning process
• Enveloped virion is released 2 consequences
• Progeny viruses are released continuously, while
  replication is proceeding w/in the cell ends
  when the cell can no longer maintain the
  integrity of the cell membrane.
• All infectious progeny are extracellular, except
  for those viruses that bud form internal
  membranes (ER or nuclear membrane)

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Replication of DNA Viruses

• Occurs w/in the host cell Nucleus
• Flow of information is from ds DNA ? mRNA ?
  Proteins
• Viral DNA resembles host DNA for transcription
  and replication
• Early Proteins set the stage for nucleic acid
  synthesis
• Transcription of Viral Genome
• Initially uses host cells DNA-dependent RNA
  polymerase
• Results in m-RNA, which is translated into
  NON-structural viral proteins (not part of virus
  structure used for the continuation a nucleic
  acid synthesis ENHANCEMENT of host cells
  ability to replicate viral DNA)
• DNA binding proteins
• Cellular growth promoters/activators
• Transcriptional activators
• Viral DNA-dependent DNA polymerase
• DNA synthesis primers

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Replication of DNA Viruses

• DNA Replication
• Semiconservative replication of viral DNA
• Catalyzed by viral-based DNA-dependent DNA
  poymerase
• Def. Semiconservative Replication replication of
  DNA molecule yielding 2 daughter duplexes, each
  consisting of ½ parental DNA (one strand of the
  original duplex) ½ new material ½ of the
  original material is conserved in each of the 2
  copies.
• Initiated by viral based primers
• Late Proteins
• Transcription of viral genome to produce mRNA,
  which is translated into
• Structural Proteins ? make up the
  capsid/capsomere proteins
• Viral enzymes
• Note pool of DNA that is transcribed ?
  translated into pool of viral proteins (products)
  finally makes up the nucleocapsid w/ viral DNA
  contained inside.

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Replication of DNA Viruses

• Special case of DNA viruses Viruses w/ partially
  dsDNA gt Very unique!!
• The relaxed circular genome is repaired and
  converted to a closed circular (supercoil) form
  by virion-associated DNA polymerase
• Genome is transcribed into
• mRNA that make proteins
• Genomic length RNA that serves as a template for
  the synthesis of genomic DNA by a virion-encoded
  RNA-dependent DNA polymerase (Reverse
  Transcriptase) e.g., Hepadnaviridae (HBV) RNA ?
  DNA

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Replication of RNA Viruses

• Occurs w/in the host cell Cytoplasm
• Replication of genome takes place via
  double-stranded replicative intermediates
• Early proteins for primers of RNA synthesis,
  not structural proteins
• Positive-stranded RNA (RNA viruses w/ () sense
  RNA) mRNA or Messenger Polarity
• Often translated into a polyprotein
• Postranslation modification into structural
  non-structural proteins
• Synthesis of RNA-dependent RNA polymerase that is
  responsible for synthesis of Complementary
  genomic length (-) sense RNA molecules, which
  are used as a template to generate more messenger
  molecules for synthesis of virus-specific
  proteins or can be used for the production of ()
  sense progeny of the genome
• Is INFECTIOUS

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Replication of RNA Viruses

• Summary of Positive Polarity RNA Viruses
• RNA viruses with a single-stranded genome of ()
  polarity replicate via a complementary (-)
  stand intermediate
• Genome is the messenger sense mRNA is
  infectious
• The RNA can directly act as a mRNA molecule and
  can be translated directly to produce a
  polyprotein, from which RNA-dependent RNA
  polymerase is cleaved
• RNA-dependent RNA polymerase synthesizes
  complementary (-) ssRNA, serving as templates
  for synthesis of progeny () strands ? additional
  mRNAs
• w/ sufficient quantity of capsid protein
  produced, progeny () ssRNAs assembled into
  nucleocapsids

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Replication of RNA Viruses

• Occurs w/in host cell Cytoplasm
• Early Proteins
• Negative-stranded RNA (RNA viruses w/ (-) sense
  RNA) template for mRNA
• NOT infectious
• Viruses carries its own RNA-dependent RNA
  polymerase
• Production of () sense RNA, which acts as an
  mRNA
• mRNA is translated in proteins and progeny (-)
  stranded RNA

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Replication of RNA Viruses

• Summary of Negative Polarity RNA Viruses
• Viruses w/ ssRNA genome of (-) polarity
  replicate via a complementary () strand
  intermediate
• genome is in the anti-messenger sense (-)
• The RNA genome CANNOT directly act as a mRNA
  molecule, and therefore, cannot be directly
  translated into protein host cell has no enzyme
  capable of this translation either.
• The genomic RNA is not infectious
• Synthesize genomic length () sense RNA molecules
  that serve as a template to produce genomic
  length (-) sense molecules for incorporation into
  progeny virions
• Contain a virion-associated transcriptase
  RNA-dependent RNA polymerase, which transcribes
  (-) RNA genome into () RNA molecule (mRNA),
  which are then transcribed into viral proteins
  and progeny (-) strand RNA molecules that can be
  packaged into virions.

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Replication of RNA Viruses

• Summary of Viruses w/ a dsRNA genome
• Segmented genome, with each segment coding for
  one polypeptide
• Viral mRNA transcripts are produced by a
  virus-coded, RNA-dependent RNA ploymerase
  (transcriptase)
• Fates of the produced () RNA transcripts
• Translation into viral proteins
• Templates for complementary (-) strand synthesis,
  resulting in formation of dsRNA progeny

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Replication of RNA Viruses

• Summary of Viruses w/ a genome of ssRNA of ()
  polarity
• Replication occurs via a DNA intermediate
• Conversion of a () strand RNA to a dsDNA
  accomplished by an RNA-dependent DNA polymerase,
  commonly known as Reverse Trasnscriptase, which
  is contained in the virion
• Resulting dsDNA becomes integrated into cell
  genome by action of viral integrase
• From integrated DNA, viral mRNAs and progeny ()
  strand RNA genomes are transcribed by host cell
  RNA polymerase

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Effects of Viral Infection on Host Cell

• Viral Infections in which no progeny viruses are
  produced
• Infection Abortive
• Virus is lacking enzymes, promoters,
  transcription factors, etc. for complete viral
  replication host cells are non-permissive
• Infection by a defective virus of a cell that
  normally supports viral replication
• Death of the cell as a consequence of infection
• Viral Infections in which the host cell may be
  altered antigenically but is not killed, although
  progeny virus are released
• Host cell is permissive infection occurs, but
  viral replication and release neither kills the
  host nor interferes w/ its ability to multiply
  are carry out its functions
• Infection Persistent

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Effects of Viral Infection on Host Cell

• Viral Infections that result in a latent state in
  the host cell
• Persistence of viral genome in host cell w/ no
  production of progeny virus Latent Virus
• Can show up months or years later, leading to
  productive infection
• Viral Infections resulting in host cell death
  production of progeny virus
• Typical result of progeny-yielding infection by
  cytocidal virus shut-off host cells
  macromolecular syntheses by one or more of the
  viral gene products, resulting in host cell
  death.
• Infection Lytic

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Viral Persistence

• Host Cell Categories
• Permissive Cells
• Provide all of the necessary factors for
  immediate replication of a particular virus
• Permits replication
• Semipermissive Cells
• Processes that support virus replication are slow
  or inefficient
• Partial support of viral replication
• Latent-persistence virus expressed only in
  growing cell, or in a stimulated cell
• Non-permissive Cells
• Does NOT allow replication of a particular virus
• Viral DNA can penetrate and get incorporated into
  host genome
• Transformation Immortalization form basis for
  oncogenesis get tumor formation (malignancy)
• Continual unregulated growth of cells w/ ?s in
  morphology loss of contact inhibition
• Viral basis to cancer e.g., Human Papilloma
  Virus (HPV)

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Chapter 24 Non-Enveloped DNA Viruses

• 3 major Non-Enveloped DNA Virus Families
• Papovaviridae
• Adenoviridae
• Parvoviridae

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Papovaviridae

• Family Papovaviridae
• Subfamily Papillomavirinae
• General characteristics of Papovaviruses
• Small, Non-enveloped (naked) viruses
• Icosahedral nucleocapsids
• Doubled-stranded, circular DNA (cDNA)
• Unique to Papovaviruses
• Encodes proteins that promote cellular growth
• Cannot be easily grown in tissue culture

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Papovaviridae

• Subfamily Papillomavirinae
• All papillomaviruses induce hyperplastic
  epithelial lesions in their host species
• gt100 types (species) of HPVs identified based
  on differences in DNA base sequences
• HPVs display great tissue cell specificity
• Affinity for surface epithelia of skin mucous
  membranes
• Varying potentials to cause malignancies (cancer)
• Cervical carcinoma high risk
• Condyloma acuminata (anogenital warts) - common
  STD w/ low frequency of progression to malignacy
• Laryngeal papillomas m/c benign epithelial
  tumor of larynx low frequency of progression to
  malignancy
• Common, flat and plantar warts all associated
  w/ benign lesions ONLY

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Papillomavirinae

• Epidemiology
• HPV transmission via person-to-person direct
  contact
• Sexual intercourse w/ infected individual
• Contaminated surfaces (fomites)
• Communal bathroom floors
• Delivery thru infected birth canal
• Mother ? Infant transmission
• Contact w/ epithelial surface lesions, such as
  abrasions

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Papillomavirinae

• Pathogenesis/Cellular Affinity
• Lytic infections in permissive cells (epithelial
  cells)
• Viral DNA becomes a plasmid in Basal Layer of
  skin mucous membranes
• Viral genome is maintained in low copy s as a
  plasmid in nuclei of multiplying basal cells
• Cells grow differentiate into epithelial cells,
  begin to express Keratin synthesis also
  transcribe viral DNA, increasing production of
  virus
• Early Viral Proteins E1 E2 gt ?epithelial cell
  proliferation formation of benign tumors

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Papillomavirinae

• Pathogenesis/Cellular Affinity
• Wart formation in cutaneous tissue
• D/t cell multiplication delayed differentiation
  induced by certain Early viral proteins
• Viral infected cells leave basal layer, spread
  laterally and then migrate toward surface of skin
• Viral cycle proceeds in parallel with steps of
  keratinocyte differentiation, which end w/
  terminally differentiated stratum corneum growing
  a wart
• Excess keratin is synthesized along w/ continued
  cell proliferation
• Result thickened cornified layer w/ dead cells
  containing virus
• Virus cycle begins w/ expression of viral early
  genes ? early proteins then multiplication of
  viral genome then assembly of virus progeny in
  superficial layers of wart

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Papillomavirinae

• Pathogenesis/Cellular Affinity
• Oncogenically transforms non-permissive cells
• Immortalize/kill non-permissive cells get tumor
  formation
• Result of integration of viral DNA into host cell
  DNA (Transformation)
• Activation of E6 E7 Viral genes (oncogenes) to
  produce a protein that INACTIVATES host cells
  normal growth suppressor genes, p53 p105
• Result uncontrolled cell growth many
  mutations
• E6 binds to p53 E7 binds to p105
• Turn off normal growth suppression activity ?
  ?cell growth ? tumor formation
• Def. Oncogenes genes involved in control of cell
  growth when defective cause cells to
  proliferate abnormally form a tumor

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Human Papilloma Virus (HPV)

• General Characteristics
• Member of Papovavirus family
• gt100 distinct types
• Circular ds-DNA
• Very dependent upon host cell for transcription
  of viral genome
• Infect are replicated by squamous epithelial
  calls of skin mucous membranes
• WARTS in skin
• PAPILLOMAS on mucous membranes
• Infected cells exhibit nuclear ?s w/ large
  perinuclear vacuoles
• Result Koiliocytosis cytoplasm shrinks away
  from area around the nucleus
• Koiliocytes enlarged keratinocytes w/ clear
  haloes around shrunken nuclei

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Human Papilloma Virus (HPV)

• Clinical Significance
• Cutaneous Warts (HPV 1?4) m/c type
• Common fingers, arms
• Plantar soles (bottoms) of feet
• Flat arms, face, knee
• Epidermodysplasia verruciformis
• In pts w/ inherited predisposition for multiple
  warts that do not regress, but spread to many
  body sites
• May give rise to squamous cell carcinomas, esp.
  in sunlight-exposed areas of skin

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Human Papilloma Virus (HPV)

• Clinical significance
• Head neck tumors (benign)
• Oral papillomas benign epithelial tumors of oral
  cavity
• Laryngeal papilloma (HPV-6, 11) benign
  epithelial tumors of larynx
• Mucosal infections greatest clinical importance
  are those of genital tract
• Anogenital warts (condylomata acuminata) HPV-6,
  11 exclusively on squamous epithelium of
  external genitalia perianal areas transmitted
  sexually
• Cervical Dysplasia and Neoplasia in ?s
• HPV-16, 18 gt cause cervial papillomas
  dysplasia most transforming of the HPV types
• Virus DNA in integrated into host genome
• E6 E7 oncogenes produce proteins that bind to
  inactivated cellular growth suppressor proteins
  (p53 p105) ? cervical cancer/carcinoma
• NOTE When ? genital tract infected associated
  w/ intraepithelial cervical neoplasia and cancer
  1st neoplastic ?s dyplasia, as viewed under a
  light microscope (from PAP smear)

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Papillomavirinae

• Laboratory Identification
• Cutaneous warts ? visual identification
• Cytology detection of koiliocytotic cells
• Observed in PAP smears
• PAP smears detect HPV-16 of HPV-18 by presence of
  koiliocytotic (vacuolated cytoplasm) squamous
  epithelial cells, which are round 7 occur in
  clumps
• Thus, determination whether HPV present in
  abnormal tissue recovered by biopsy of cervical
  swab (PAP smear), and whether HPV detected is _at_
  high risk of malignant transformation
• More specific techniques include
• In situ DNA probe analysis
• PCR
• Southern Blot Hybridization
• Immunofluorescence
• Electron microscopy

40
Papillomavirinae

• Treatment Prevention
• Treatment of warts surgical removal or
  destruction of wart tissue w/ liquid N, laser
  vaporization, or cytotoxic chemicals
• Common warts can regress spontaneously
• Prevention via
• avoidance of the opportunity for contact w/ wart
  tissue
• All procedures for prevention of STDs
• Host defense mechanisms against HPV are not well
  understood, but Cellular Immunity is important in
  control of HPV infections

41
Adenoviridae

• Family Andenoviridae
• Subfamily None
• General characteristics of Adenoviruses
• Linear, ds-DNA
• Non-enveloped, icosahedral, or cubical shape
• NOT destroyed in environment remains stable
  infectious, thus easily transmitted (Naked
  virion)
• Commonly cause URT infections, gastroenteritis,
  conjunctivitis
• Named b/c virus was 1st isolated from the tonsils
  adenoids (nasopharyngeal lymphoid tissue)
• 42 serotypes (species) of human adenoviruses are
  known in groups A ? F, based on DNA homology
  hemagglutinin patterns

42
Adenoviridae

• General characteristics of Adenoviruses
• Vertices exhibit VAPs as fibers or spikes
• Determine tgt. cell specificity among the
  serotypes
• Possess HEMAGGLUTININ a type-specific viral Ag
• Hemagglutination (clumping of RBCs) occurs b/c
  of presence of hemagglutinin Ag viral
  fibers/spikes
• Capsid proteins gt toxic to host cell
• Viral genome encodes many proteins
• Early proteins promote growth of infected cell
• Provides for ?wn DNA-dependent DNA polymerase
  to be used in replication of genome
• Some proteins suppress host IS response,
  including inflammation
• Virus enters host cell by receptor mediated
  endocytosis

43
Adenoviridae

• Epidemiology
• Adenovirus transmission Person-to-person, direct
  indirect
• Respiratory (airborne) route all ages affected
• Respiratory droplet (aerosol)
• Fecal-oral route m/c in children
• Close person-to-person contact
• Contact w/ contaminated objects (fomites)
• Major route of transmission for eye infections
• Direct autoinnoculation by virus-contaminated
  hands, ophthalmologic instruments, or bodies of
  water in which groups of children play/swim
  together

44
Adenoviridae

• Pathogenesis
• Virus infects Lymphoid tissue, Respiratory
  Epithelium, GI epithelieum, and Conjunctiva
• Permissive cells will ultimately exhibit lysis
  death
• Non-permissive cells exhibit latency
• Mostly in lymphoid tissue tonsils, adenoids,
  Peyers Patches
• Replication via general model for DNA viruses
• Attachment to host cell receptor via knobs on
  tips of the viral fibers
• Entry into cell by receptor-mediated endocytosis
• Uncoating of viral genome, transported to nucleus
  of host cell
• Transcription of viral genes, genome replication,
  assembly all occur w/in Nucleus
• Cytopathology (CPE)
• Histological Hallmark gt dense, central,
  intranuclear inclusion bodies w/in an infected
  epithelial cell composed of DNA protein

45
Adenoviridae

• Clinical Significance
• Observed disease sxs are related to the killing
  of epithelial cells systemic infections are rare
• Most adenovirus infections are asymptomatic
• Certain types of adenovirus are m/c than others,
  producing disease
• Adenoviruses primarily infect children less
  commonly infect adults

46
Adenoviridae

• Clinical Significance
• Acute Respiratory Infection (serotypes 4 ? 7)
• m/c clinical disease of infants young children
• Often mimics common cold
• Sxs
• Sore throat
• Cough
• Fever (Note common cold seldom has a fever)
• Runny nose (coryza)
• HA, cervical adenitis, laryngitis, croup,
  bronchiolitis
• Def. Coryza acute inflammation of nasal mucosa,
  accompanied by profuse nasal discharge
• Def. Croup and acute viral disease of children,
  marked by a resonant barking cough, suffocation
  and difficult breathing, and laryngeal spasm b/c
  of respiratory distress

47
Adenoviridae

• Clinical Significance
• Pharyngoconjunctal Fever
• Pharyngitis accompanied by conjunctivitis
• Prevalent in school-aged children
• Occurs both sporadically in outbreaks, often
  w/in families or in groups using the same
  swimming facility (swimming pool
  conjunctivitis)
• Keratoconjunctivitis
• Severe infection of the eyes
• Inflammation of the eyelids eyelids turn under
• Gastroenteritis Diarrhea (Serotypes 40,41,42)
• Acute viral gastroenteritis
• Most human adenoviruses multiply in GIT can be
  found in stools
• Route of transmission p-p, indirect, fecal-oral

48
Adenoviridae

• Clinical Significance
• Acute Hemorrhagic cystits
• seen mostly in children (boys) virus gets into
  blood ? settles in bladder and get inflammation,
  bleeding into bladder and blood in urine
  (hematuria)
• Systemic Infection in immunocompromised pts
• Viremia occurs virus gets into the blood
• Acute Febrile Pharyngitis (serotypes 1? 7)
• Sxs
• Nasal congestion
• Cough
• Coryza
• Malaise
• Fever
• Myalgia
• HA
• Pharyngitis
• With no other symptoms, often mimics
  Streptococcal disease (severe sore throat)
  Strep. pyogenes

49
Adenoviridae

• 2 Immune System Avoidance Mechanisms
• Adenoviruses prevent the expression of Major
  Histocompatibility (MHC) Class I Ags on surface
  of infected cells, thus serving as an IS
  avoidance mechanism
• Adenoviruses are NOT affected by Interferon,
  released by virally infected cells

50
Adenoviridae

• Laboratory Identification
• Virus isolation NOT done on a routine basis
• Identification done by neutralization of
  humagglutination inhibition using type-specific
  antisera
• Direct test of stool specimens by ELISA
• Immunity
• Specific humoral immunity (Ab) in response to
  lytic infection gt necessary for resolution
  prevention or re-infection
• Cell-mediated immunity gt necessary to prevent
  viral spreading or outgrowth
• Treatment Prevention
• No antiviral agents available to treat infection
• Live, attenuated adenovirus vaccine is available
  for prevention of epidemic respiratory disease

51
Parvoviridae

• Family Parvoviridae
• Subfamily None
• Parvovirus B19 ONLY member known to cause Human
  disease
• General Characteristics of Parvoviruses
• Very small, non-enveloped, icosahedral
• Linear, ss-DNA
• SMALLEST of DNA VIRUSES
• Small genome makes these viruses very dependent
  on host cell for replication
• Some virus particles contain () strand, others
  (-) strand
• ONLY () stranded viruses are infectious
• Virus does NOT provide it own DNA-dependent DNA
  polymerase
• Depends on host cell uses host cells DNA-dep.
  DNA pol to make mRNA template

52
Parvoviridae

• General characteristics of Parvoviruses
• B19 virus replicated in mitotically active cells
  and has affinity for cells of Erythroid lineage
• Human Bone Marrow cells
• Erythroid cells from fetal liver
• Erythroid leukemia cells
• B19 virus causes transplant aplastic crisis w/
  SCD and chronic hemolytic anemia and implicated
  in adult acute polyarthritis
• Parvovirus B19 virus etiological agent of
  common clinical childhood disease known as
  Erythema Infectiosum or 5ths disease
• Mild febrile exanthematous dis the occurs in
  children was the 5th chilhood exathem discovered
  (1st 4 1. Varicella, 2. Rubella, 3. Roseola,
  and 4. Measles)

53
Parvoviridae

• Epidemiology
• B19 virus is widespread
• Infections occur thru-out the year in all age
  groups
• Mcly seen in outbreaks in schools
• Common infection in childhood
• Mode of Transmission p-p, direct, respiratory
  droplets and indirect via fomites
• Viruses are stable in environment thus,
  contaminated surfaces also involved in
  transmission
• Sibling transfer is important
• Source of maternal infection during pregnancy
  mothers older child
• Transmission from pts w/ aplastic crisis ?
  members of Hx staff

54
Parvoviridae

• Review of Virus Cycle for Parvoviruses
• VAPs bind virus to P Blood group receptors on
  eryrthroid precursor cells (P Blood grp Ag)
• Penetration is a type of Viropexis
• Virion is uncoated in host cell nucleus
• Host cell polymerase produces a Complementary (-)
  strand of DNA, providing a ds molecule for
  transcription of early late viral proteins
  (mRNA for non-structural and structural capsid
  proteins)
• mRNA is translated in cytoplasm (on Ribosomes)
  and protein products are returned to nucleus for
  assembly
• During assembly, structural (capsid) proteins
  enclose both () and (-) DNA strands separately,
  giving particles w/ ssDNA
• Non-structural virus products cause nuclear
  membrane cell membrane to degenerate, releasing
  virus by LYSIS

55
Parvoviridae

• Pathogenesis of Parvovirus B19
• Virus 1st replicated in Upper Respiratory Tract
• Affinity 1st for URT epithelial cells
• Then virus gets into the blood viremia
• Viral spread in blood to Bone Marrow other
  erythroid precursor cells
• Virus is cytolytic for these cells
• B19 disease is determined by direct killing of
  these cells the subsequent Immune response
  (RASH Athralgia)
• Killing of cell release of virus activates host
  IS response, forming basis for rash and
  arthralgia

56
Parvoviridae

• Clinical Disease
• Erythema Infectiosum (5ths Disease)
• Characteristic rash, giving a slapped cheek
  appearance
• Occurs about 2 weeks after exposure
• Incubation Period virus shed into the blood
• Viremia occurs in 8 days
• Pt is infectious
• Prodromal Period once virus into blood, rash
  starts on face in children
• Non-specific influenza-like sxs (mild) fever,
  chills, sore throat, some malaise
• Slight drop in Hb levels
• This is the initial febrile period
• Pt still infectious for up to 14 days
• Symptomatic Stage get IgM Ab (ICs)
• As IgM Abs resolve the viremia, it creates
  Immune Complexes (ICs) the ppt. out in the skin
  and joints, forming basis for rash and arthralgia
• Rash appears on face spread to extremities (1-2
  wks in children)
• Adults rash may or may not occur, but is
  followed by polyarthritis of hands, wrists, knees
  and ankles

57
Parvoviridae

• Clinical Disease
• Aplastic Crisis
• Erythrocyte and platelet levels drop
• Occurs in patients suffering w/ chronic hemolytic
  anemia (e.g., SCA or SCD)
• Results form the reduction in erythropoeisis in
  Bone Marrow
• Leads to reticulocytopenia decrease in Hb
  levels, lasting 7-10 days
• Accompanied by fever, malaise, myalgia, chills,
  itching and maculopapular rash w/ arthralgia
• Hydrops Fetalis
• Aplastic crisis in fetus of pregnant ?s who are
  seroneg.
• B19 infection of seroneg. mother ?s risk for
  fetal death
• Virus can infect fetus kill erythrocyte
  precursors, causing fetal anemia CHF in utero

58
Parvoviridae

• Laboratory Identification/Dx
• Mostly based upon clinical presentation b/c of
  presence of exanthem
• Detection of viral proteins
• 1 test for Ab ELISA test for B19 IgM or IgG
• PCR (to amplify DNA) coupled w/ gene probes
  very sensitive in B19 genome detection
• Treatment Prevention
• No antiviral or vaccine available
• Good hand-washing and not sharing drinks