HC14: Viruses

Viral diseases

Viral infections are much more common than bacterial infections. Viruses are a major cause of human disease:

• Common cold: rhinoviruses, coronaviruses
• The flu: influenza
• Stomach flu: norovirus
• Fever blister: herpes simplex virus
• Meningitis or poliomyelitis: enterovirus
• HIV-AIDS
• Congenital CMV, rubella
• Et cetera

A virus is a small infectious agent that replicates only inside the host cell. It is a package containing either DNA or RNA (not both), but it is not a cell → it doesn't have organelles and fission. Surface components determine attachment to cell types.

Two important facts about viruses:

• Al viruses are obligate parasites that can only replicate in a cell
• All viruses are parasites of the host protein synthesis machinery → they must make mRNA that can be translated by host ribosomes
  • Viruses use the host cell to make proteins from their mRNA

Viruses are classified by comparing morphology and replication cycles. This provides common basis for naming and allows common clinical approach.

Viral structure

There are very large and very small viruses. Viruses with a larger genome are more complex.

A virus can be naked or enveloped:

• Naked virus
  • Capsid
  • Nucleic acid
• Enveloped virus
  • Envelope
    • A lipid bilayer containing spikes
    • Surrounds the capsid
  • Capsid
  • Nucleic acid

Terminology:

A few important terms that are used to determine the structure of a virus:

• Nucleic acid: DNA or RNA genome
• Capsid: protein structure surrounding the nucleic acid
• Nucleocapsid: capsid + nucleic acid
• Capsomere: subunit of the capsid

Capsid:

Capsid viruses have a symmetrical arrangement:

• Helical
• Icosahedral: 20 triangular seats

Capsid functions are:

• Packaging of viral parts
• Protection of nucleic acids
• Transport of nucleic acids from cell to cell
• Provision of specificity for attachment to the cell
  • Spike proteins

Envelope:

The basic structure of an enveloped virus is as follows:

• Center with DNA or RNA
• A protein coat (capsid)
• A lipid membrane envelope

Capsid versus enveloped viruses:

Capsid and enveloped viruses differ from each other in multiple ways:

• Naked capsid virus
  • More resistant to environmental conditions
    • Drying
  • More difficult to kill with detergent
  • Sensitive to:
    • Chlorine and iodine
  • Enters the host cell by virus-induced endocytosis
  • Exits the host cell by cell lysis
• Enveloped virus
  • More susceptible to environmental conditions
  • Easier to kill with lipophilic detergentia than non-enveloped viruses
  • Sensitive to:
    • Chlorine and iodine
    • Ethanol or propanol 70-95%
    • Chlorhexidine 0,05-0,5%
    • Ammonium, phenol
  • Enters the host cell by membrane fusion or endocytosis
  • Exits the host cell by budding

DNA and RNA

A virus is either a DNA or an RNA virus. It never can have DNA and RNA simultaneously.

DNA viruses:

General properties of DNA viruses are:

• Resemble host cell DNA
• Processing occurs within the host cell nucleus
• Relatively stable within the cell → can persist easily
• Usually have large and complex genomes
• Low frequency of mutation

A few human DNA viruses are:

• Herpes viruses
  • Cytomegalovirus (CMV)
  • Epstein-Barr virus (EBV)
  • Herpes simplex virus
  • Varicella zoster virus
• Hepatitis B virus

RNA viruses:

General properties of RNA viruses are:

• RNA is labile and intended to be transient
• Persisting infections are unusual
  • But there are always exceptions
• Processing occurs in the cytoplasm
• RNA viruses must encode an enzyme to replicate RNA
  • The host cell cannot do this, but the host machine can make this protein
  • RNA-dependent RNA polymerase
• High frequency of mutation

RNA viruses can be:

• Positive stranded
• Negative stranded

Positive and negative viruses are distinguished from each other because they have a different process of replication.

A few human RNA viruses are:

• Enterovirus group
  • For example the poliomyelitis virus
• Human immunodeficiency virus (HIV)
• Influenza virus
• Respiratory Syncytial (RS) virus

Viral replication

A virus needs a host cell to replicate. The viral replication cycle consists of:

1. Entry
   • A specific interaction between the cell surface structure and the virus occurs
     • Specific viruses can only attach to specific cells
   • Enveloped viruses enter the cell via membrane fusion or endocytosis
   • Naked capsid viruses enter the cell via endocytosis
2. Replication
   • The genome is replicated
   • The protein is produced
3. Exit (or not)
   • Naked capsid viruses exit via cell lysis
   • Enveloped viruses exit via budding
     1. When the virus arrives at the membrane, it is engulfed by a lipid bilayer → it takes a little of the host membrane + spikes with it → a new virus particle is created
        • The cell membrane already has spikes from the virus proteins

Viral pathogenesis

Survival of the fittest:

The Darwinian theory survival of the fittest can also be applied to viruses:

• Viruses depend upon the host to survive → a smart virus doesn't kill its host
• If viruses are too successful and kill their hosts, they may eliminate themselves
• If viruses are too passive, the host's immune system may eliminate them
• Viruses have several survival strategies
  • A high number of mutants → antigenic drift
    • RNA-viruses can change to escape from immunity → new viruses circulate every year
  • Remain latent in the host, to reactivate and be transmitted again at later time points
    • HSV and VZV

Tropism:

Viruses only infect certain cells in the human body, the cells in which it can replicate. This concept is called tropism.

Cellular damage:

Viruses often lead to cellular damage:

• Lysis: cell death by viral replication
• Immunopathology: cell death by an immune reaction of the host
• Tissue damage and organ dysfunction
  • Vesicles, jaundice, et cetera

Natural course of viral infection:

An acute viral infection can lead to 3 things:

• Clearance from the body
  • Enterovirus
  • Influenza virus
  • RS virus
• Chronic persistent infection: active replicative state
  • Chronic HBV
  • HIV
• Latency: inactive state
  • All herpes viruses

Diagnosis:

There are 2 ways to diagnose a viral infection:

• Clinical diagnosis
• Laboratory tests
  • Genome amplification and detection
    • With PCR
  • Antibody detection
    • Indirect approach
    • Dependent on host immunity
  • Viral culture
    • Laborious approach → takes a lot of time
    • Growth not always possible
  • Electron microscopy
    • Laborious approach

Varicella Zoster virus

The Varicella Zoster virus (VZV) is a herpes virus. It is an enveloped DNA virus. Replication takes place in the nucleus. A patient has localized symptoms, on one side of the body:

• Pain
• Shingles: vesicles, papules, crusts

The virus has 3 phases:

1. Chickenpox/varicella
   • Usually in the first 5 years of life
2. Latency
   • The virus resides in a dorsal root ganglion
3. Herpes zoster/shingles
   • The virus is reactivated

In conclusion, the patient has a reactivated chickenpox virus. The diagnosis can be made clinically or by VZV DNA detection.