Lecture 28 Flashcards
What are the problems and difficulties associated with anti-viral therapy?
Most viral infections are not detected until late in the course of the disease
Viruses hijack host cells making it hard for the immune system to distinguish between ‘friend’ and ‘foe’
Viral infection may be associated with massive, overwhelming proliferation of viral particles
Viruses have a very rapid mutation rate helping them to evade the immune system and making vaccines difficult to develop
Some viruses use subversion measures to interfere with the host’s immune response
Some viruses can integrate their genetic material into host chromosomes to cause latent infection
What are the four types of anti-viral therapy?
Reverse transcriptase inhibitors protease inhibitors absorption and fusion inhibitors anti-viral cytokine therapy Once again selective toxicity is achieved through identification of differences between viral replication processes and humans, however this is not as selective as in antibiotics
What is the life cycle of the HIV virus?
Binds to cell surface
Entry of virus into cytoplasm
Uncoating of viral RNA
Viral Reverse transcriptase produces viral DNA
this is integrated into the host genome
Host mechanisms are used to multiply and produce viral mRNA
translation of viral proteins from mRNA
processing of viral proteins (glycosylation, trimming etc)
assembly of progeny virions at cell membrane
release of progeny by budding
What are the main chemotherapeutic targets for the HIV virus?
Conversion of RNA to DNA (reverse transcriptase inhibitors)
Protein assembly and packaging (protease inhibitors)
Fusion inhibitors (latest)
What are the goals of anti-HIV therapy?
Maximal and durable suppresion of HIV viral load
restoration and/or preservation of immunological function
improvement of quality of life and reduction of HIV related morbidity and mortality
Virustatic- does not cure
What is HAART and why is it used?
Highly Active Anti-Retroviral Therapy when a patient is one a combination of 3 or more antiviral drugs in the hope that this will prevent the development of resistance as this can rapidly develop if only one drug is used
What are the features of nucleoside reverse transcriptase inhibitors?
First class of anti-HIV drugs developed Block conversion of viral RNA to DNA via reverse transcriptase Prodrugs which are converted by intracellular enzymes with 3 successive phosphorylations to 5'-triphosphate metabolites The metabolite is incorporated into the DNA chain and terminates it
What side effects are associated with zidovudine?
Haematological toxicity, pancreatitis, liver damage and severe anaemia
What is the pathway which converts AZT from a prodrug into an active metabolite?
3 phosphorylations first by dThd kinase, then dTMP kinase then NDP kinase
What are non -nucleoside reverse transcriptase inhibitors?
Compounds that target steps of the viral life cycle that are not involved in RNA to DNA conversion such as protease inhibitors and fusion inhibtors
These compounds must be more carefully designed and therefore are frequently more selective than NRTIs
An example of NNRTI is nevirapine which can have serious side effects like life threatening skin reactions and liver damage
What are the features of protease inhibitors?
Block the processing of viral protein, and thus assembly of the virion
Bind to the active site of the protease inhibiting its function so proteins are left uncleaved and inactive
Have nausea, vomiting and diarrhoea as side effects
Example is Saquinavir
What are fusion inhibitors?
Compounds such as enfuvirtide which inhibits the entry of HIV into host CD4 lymphocytes
Have flu like symptoms, changes in mood, GI effects, headaches and dizziness, hypersensitivity reactions
What is cytokine therapy?
Use of naturally occurring hormones such as the glycoprotein IFN-Alpha that is normally secreted by cells in response to viral infections
Augments the host immune system and targets cell killing by lymphocytes and inhibition of viral replication in infected cells
various recombinant forms are used to treat viral hepatitis
Requires subcutaneous administration at least 3 times a week for chronic hepatitis C treatment
What are the major side effects of using interferon-alpha in therapy?
Fatigue Depression Flu-like symptoms Nausea Diarrhoea Appetite loss
