L09: HIV Mutations Flashcards
Why are RNA viruses more prone to mutation than DNA viruses
RNA viruses get transcribed by RNA polymerase which do not point read and this leads to point mutations occuring.
DNA viruses are transcribed by DNA polymerase which proofread.
What is an acute infection
Immune responce may clear individual viruses by variations can re-introduce the virus
What is an chronic infection
Viruses persist changes within the course of infection
Ongoing ping infection due to new variations
What is an antigenic drift
One virus has point mutations due to no proofreading and replicates to give new variant
What is antigenic shift in influenza
2 or more viruses exchange RNA fragments and change haemoglutinin on their surface
This generates a new virus
What does antigenic shift result in
Pandemics
Why do we not have antigenic shift seen in MMR
Genomes are non segmented so you do not get exchange of segments in the virus
Does HIV have a cure
No
What are the glycoproteins of HIV called
GP120
GP41
Which receptors does glycoproteins bind to
CD4 receptor
CXCR4
CCR5
Describe the HIV lifecycle initial stages
1) HIV attaches and fuses into the host cell
2) Viral RNA is synthesised to double stranded DNA by reverse transcriptase
3) viral dna is delivered to the nucleus of cell
Where does GP120 bind to
CD4 receptors on T cells
What are the coreceptors of CD4 T cell surface membrane
CXCR4
CCR5
Describe what happens when HIV bins to CD4 receptors on T cell
1) gp120 binds to CD4 receptors
2) this triggers confomational change in gp120
3) This enables GP120 to bind to its coreceptors CCR4 or CCR5
4) this triggers further conformational changes to move GP120 out of the way
5) so GP41 can penetrate into the cell membrane
6) this brings the HIV envelope with close proximity of cells membrane which causes the fusion of the HIV into the cell.
What is the stucture of the hiv glycoproteins
GP41 attached to GP120 which is protruding out
What happens when the virus has got into the CD4 T cells
Viral RNA undergoes reverse transcription to form double stranded DNA
Double stranded DNA enters nucleus
What happens to the double stranded DNA when it enters the nuclues
Integrated into the host genome straight away by enzyme integrate
What does the integration of hiv dna into the host genome mean
You cannot get rid of the virus so it is permanent
What are the two pathway that can occur when the dsDNA is intergrated into the host genome
Enter latency
Or
Enter productive cycle
Describe the productive cycle
Pro-virus DNA is transcribed by MRNA
MRNA is translated To new proteins
Proteins are assembled
New virus is released
What are 5 key staged where we can interrupt virus replication and entry
1) binding
2) fusion
2) reverse transcription
4) integration
5) maturation
Why type of therapy do use to treat HIV
Multi drug therapy
Give an example of a multi drug therapy
2 different NRTIs + 1 NNTRI
Or
2 different NRTIs + 1 protease inhibitor
What does NRTI stand for
Nucleoside reverse transcriptase inhibitors
Give an example of NRTI
Zidovudine
What is the mechanism of action of NRTI
Incorporate into virus dna because it is a nucleoside
Becomes a chain terminator
Inhibits HIV replication
What does NNRTIs stand for
Non nucleoside transcriptase inhibitors
Give an example of NNTI
Efavironz
What is the mechanism of action of NNTI
Binds directly to reverse transcriptase to alter its shape
Nucleotides cannot interact with the enzyme to create DNA
Give an example of protease inhibitors
Saquniavir
What is the mechanism of action of protease inhibitors
As HIV replicates it produces protease, protease cleaves HIV poly proteins into structural proteins which are assembled to form new virus
Protease inhibitors bind to protease and inhibit cleavage of viral proteins
Prevent HIV from being assembled and released from infected cells.
What happens in acute infection
CD4+ T cell decline temporarily
CD8+ T cells increase to get ride of virus
Anti HIV-1 antibodies appear
What happens in chronic infection
HIV continues to replicate at low levels for a decade Gradual decline in CD4+ T cells CD8+ remain unaffected Antibodies evolve Acquisition of macrophage tropism
What will HIV turn into when CD4+ T Cells are below 200 cell/ml
AIDS
What will be seen in a AIDS blood
CD4+ T cells depletion
HIV specific CD4+/CD8+ EXHAUSTION
What are the AIDS defining opportunistic infection
Cryptococcal meningitis Toxoplasmosis Pneumocystis pneumonia Oesophageal candidiasis Certain cancers
If HIV mutation occur what clinical problem can this lead to
Drug restistance
Therefore in which drugs can you get resistance
NNRTI- reverse transcriptase is mutated do NNRTI cannot bind to enzyme
NRTI - mutation in reverse transcriptase mean you get steric hindrance And excision of NRTIs
What does excision of NRTIs involve
Pyrophosphorlysis (removes the nucleotides)
Why is it difficult to make a HIV vaccine
Genetic variability of HIV
A Glycan shielding covers the envelope glycoproteins
Immune escape: antibody resistance of the new variation of HIV so antibodies cannot neutralise mutated/new HIV
