On 9 Mar 1995, Mr Kevin Coles wrote:
> I am a biology teacher at St Alban's College in South Africa. My std
> 9 class is doing a project on Aids.
> I would appreciate any information on:
> structure
> mutation
> retrovirus
> medical breakthrough's (AZT etc)
> any other relevant biollogical info
> Thank you in anticipation
Hello. I work in a lab that studies the mutational aspects of HIV,
particularly those associated with HIV reverse transcriptase (RT). RT is
the primary source of HIV mutation within infected individuals since all
other stages of the infection cycle utilize cellular transcription and
translational machinery which has a high fidelity. RT, unlike DNA
Polymerase, has no proofreading mechanism and is rather adept at
insertion, deletion, and misincorportation.
Generally, the accepted mutation rate per base pair per replication
cycle is on the order of 1 in 10^10 (combined DNA Polymerase editing,
mismatch repair mechanisms, and excision repair). The average base
substitution rate of RT is in the order of 1 x 10^-5 per nucleotide per
replication which is extremely high.
Other mutation types that are common are frameshifts, deletions,
insertions, and recombination events which combine into the above
mentioned rate. Hypermutations that occur as G to A transitions occur in
1 out of every 10 to 30 progeny virus. With these errors, 10 to 100% of
replicating viruses will produce mutant progeny after each replication
cycle. In heterozygous, mixed infections, 1 out of every 2 to 3
replicating viruses will produce recombinant viruses.
RT can use either RNA or DNA as a template and it lacks any 3' to 5'
exonuclease activity, so it cannot correct misincorporations - its error
rate on either template is the same. RTs from different viruses exhibit
differing error rates: RT from Moloney Murine Leukemia Virus has a G to T
transversion rate of 1 in 770,000 vs the HIV-1 transversion rate of 1 in
3000. The most frequent HIV-1 RT error in vitro is base substitution due
to template-primer slippage (dislocation), and depends on the immediate
template sequence environment.
Essentially, if RT error rates observed in vitro also occur in vivo,
then all viral progeny will be different than the parental virus that
first infected the cell - and will be different from each other. This
being the case, HIV (and retroviruses in general with their error-prone
RTs) exist as swarms of closely related but genetically distinct viruses
- quasispeicies.
Patrick
