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• Viruses


  • Obligate intracellular parasites = rely on host machinery to reproduce
  • When not inside an infected cell, they're called virions
  • Single or double stranded DNA or RNA
  • Protein coat = capsid
  • Some have a lipid envelope derived from host with glycoproteins
• Viral range


  • Group of cell types that a virus can infect
  • Only infects bacteria = bacteriophage
  • Infect animals or plant = animal viruses or plant viruses
• Pathogenicity


  Ability of viruses to cause disease
• Virulence


  Degree of pathogenicity
• Latency


  • Some viruses can remain dormant in organisms
  • Chicken pox > latency in DRG > shingles
• Carriers


  People who are chronically infected
• Viral replication


  1. Absorption

  2. Penetration

  3. Replication

  4. Release
• Virus binds to host cell (determines range) > crosses membrane to nucleus > virus reacts with machinery of cell > transcription+translation of virus > new virions released
• Central dogma of biology : DNA (nucleus) > mRNA > protein (cytoplasm)
• DNA viruses


  • Enter host cell nucleus where its transcribed into mRNA by host DNA-dependant RNA polymerase, then into specific proteins
  • Poxviruses are the exception = carry their own RNA polymerase and replicate in cytoplasm without having to enter the nucleus
• RNA viruses


  • Require RNA-dependant RNA polymerases (RNA > mRNA)
  • RNA polymerase acts as transcriptase and replicase
  • Complete replication in host cytoplasm, not nucleus (only influenza in nucleus)
• Retroviruses


  • Have an RNA genome that directs formation of DNA (RNA > DNA > mRNA > protein)
  • Reverse transcriptase copies RNA into DNA (RNA-dependent DNA polymerase)
  • DNA is integrated into host then transcribed
• Prevention and therapies


  • Vaccination = cheap and effective (14 vaccines available)
  • Antivirals = exert actions at several stages of viral replication
• Acyclovir


  • Nucleoside analog (fake DNA) that viruses incorporate into their genomes
  • Lack a hydroxyl group which does DNA chain termination = life of virus halted cuz DNA inactive
  • Must be phosphorylated to acyclovir-triphosphate
  • First phosphate group = thymidine kinase (added by herpes virus)
  • Humans can't phosphorylate this, only viruses can, so doesn't interfere w/ host
  • Resistance comes from : impaired production of thymidine kinase, altered thymidine kinase, altered DNA polymerase
• HIV


  • Lentivirus = retrovirus with chronic persistent infection with gradual onset of symptoms
  • Infects human immune cells (CD4+ T cells)
  • When these get too low, body becomes susceptible to opportunistic infections (ex : AIDS)
• Highly active antiretroviral therapy (HAART)


  Drug combinations that slow the increases in viral RNA load that accompany progression of a disease
• Entry inhibitors


  • Interfere with binding of virus' gp120 proteins to CD4 and CCR5 receptors on T cells
  • Ex : Maraviroc = CCR5 receptor antagonist
• Nucleoside reverse transcriptase inhibitors (NRTI)

  • Incorporated into new HIV DNA chain, but lack a 3' hydroxyl group on ribose ring
  • Attachment of next nucleoside is impossible = chain termination
  • Mammalian cells don't use reverse transcriptase = doesn't affect host cells
• Integrase strand transfer inhibitors (INST)


  • Blocks integrase action to inhibit HIV proliferation, can't integrate into host DNA
  • Ex : Raltegravir
• Protease inhibitors


  • Virions depend on aspartate proteases which cleave precursor proteins to form the final structural proteins of mature virion core
  • Inhibitors will block this; virions can't fully mature
• Amantadine


  • Inhibits early step in replication of the influenza A virus (viral uncoating)
  • M2 protein functions as a proton ion channel required at onset of infection to permit acidification of the virus core, which in turn activates viral RNA transcriptase
• Mineralocorticoids


  Express 11β-hydroxysteroid dehydrogenase type 2 = inactivates cortisol
• Cortisol conversion


  Cortisol ⇨ cortisone
• Pseudohyperaldosteronism


  Licorice is an inhibitor of 11β type 2
• Cortisol acts on aldosterone receptors


  Causes high blood pressure
• Physiological targets and effects of GCs

  • Carb metabolism ⇨ increases circulating glucose; inhibits insulin
  • Fat balance ⇨ fat deposition in trunk but breakdown in limbs
  • Proteins ⇨ loss of muscle and bone mass in limbs
• Glucocorticoids are anti-inflammatory


  • Inhibit arachidonic acid
  • Inhibit prostanoid synthesis
• Lipocortin/Annexins


  Protein that inhibits leukocyte tissue infiltration and suppresses phospholipase A2 activity = prevents AA generation
• COX-2


  • Inflammatory mediator that turns AA into prostanoids
  • Glucocorticoids suppress transcription of COX-2 gene
  • Inhibits prostanoid synthesis = anti-inflammatory effects
• Diseases


  • Addison's disease: adrenocortical insufficiency
  • Cushing's syndrome: adrenal overactivity
• Addison's disease symptoms


  Fatigue, salt balance, sugar balance problems, skin discoloration
• Cushing's syndrome causes


  Adrenal tumour, pituitary tumour, long-term GC use, ectopic tumour
• Cushing's syndrome symptoms


  Fat in trunk, muscle loss, osteoporosis
• Pharmacological considerations of glucocorticoids

  • Allergic reactions, reduce pain after injury, gastrointestinal diseases, blood disorders, asthma, organ transplants (immunosuppressants)
• Side effects of stopping glucocorticoids abruptly

  Addison-like symptoms, hypoglycemia, low blood pressure
• Other side effects of glucocorticoids

  Hyperglycemia, immunosuppression, osteoporosis, muscle wasting
• Main applications of immunosuppressants

  • Suppression of rejection of transplanted organs and tissues
  • Suppression of Graft-Vs-Host Disease (GVHD)
  • Auto-immune diseases
• Immune response


  1. Induction phase: antigen presentation + clonal expansion

  2. Effector phase: B cells = antibodies, Th1 = cytokines + kill virally infected cells
• Inhibition of IL-2


  Activating T-cell receptor generates Ca2+ signal > activates calcineurin > dephosphorylates NFAT > nucleus > expression of IL-2
• Calcineurin inhibitors


  • Cyclosporine = inhibition of calcineurin by cyclophilin complex
  • Tacrolimus = inhibition of calcineurin by FKBP complex