Dear Virology Group,
I have thought of an new anti-HIV strategy agsint which HIV should not
be able to evolve resistance, and I am looking for feedback. Could you
please take a look at the idea and give me feedback and/or advise as to
where to post it so it can receive maximum exposure?
best
Marcos Antezana
////////////// IDEA ///////////////////
HIV relies on nuclear proteins and even packages some of them in its
viroids. If one were to mess with the latter proteins possibly already
at the viroid-stage, the virus would not be able to evolve resistance
because these proteins are nucleus-encoded and do not mutate at high
rates
one of the above proteins is a DNA mismatch repair enzyme (glycosylase,
removes uracyl from UG mismatches in DNA , I suspect it may remove other
mismatches created by reverse transcription from the DNA/RNA hybrids and
possibly from the RNA/RNA partial Watson and Crick double helices in the
viroids and in the cytoplasm upon infection)
It is very unlikely that the virus packages the glycosylase in its
viroids for something other than mismatch repair. Be this at it may,
the virus must be at a great disadvantage if it does not find the
glycosylase in the cytoplasm upon infection. Normally the glycosylase
can be expected to be found in appreciable quantities only in the
nucleus. The glycosylase packaged in the viroid must therefore be used
to create a glycosylase-rich micro-environment in the cytoplasmic region
where reverse transcription will take place.
My idea is both to increase the mutagenicity within viroids and in the
cytoplasm and, at the same time, inhibit the glycosylase activity. This
should mutate the virus to death. This could be over evolutionary time
(Eigen’s hypercycle theory) and in one just generation (unviable
viroids/reverse-transcripts) so it is very likely that the virus will be
gone if one mutagenizes it beyond a critical threshold.
More specifically, the treatment consists in using, separately if
necessary, but concomitantly for maximum effectivity:
1) a low-nuclear-penetrance mutagen, hopefully RNA-specific and
inactive on DNA, to increase the mutation rate in the RNA genomes
packaged in viroids,
and
2) a low-nuclear-penetrance glycosylase inhibitor
1. will mutagenize the virus before infection
2. will make mismatch repair after reverse transcription very
error-prone (this has been proven already)
2 will also impede that repair take place between the two RNA genomes
both within a viroid and at infection time when the two HIV genomes are
injected in the host were such repair to be happening at all.
RNA-specific mutagenicity and the low nuclear-penetrances of both
compounds are only necessary to avoid increasing the mutation rate of
nuclear DNA . But 1 is not necessary if 2 is guaranteed. Moreover 1
would allow using a mutagen that would damage the reverse transcript
also.
non-RNA-specific mutagens that can reach the nucleus and produce UG
mismatches are known and could be used, but could create problems if
they overwhelm the nuclear glycosylase by producing too many mismatches
to repair, which ultimately should cause cancer.
it should be easy to create low nuclear-penetrance constructs: bind the
mutagen or the inhibitor at the tip of short elongated lipophilic
molecules that would penetrate the viroids but that would have a bulky
plug at the end so they cannot be fully absorbed through membranes.
a presence restricted to the proximity of the interior surface of cells
and viroids should be enough for the mutagens/inhibitors to enter into
contact/damage the viroids’ contents while guaranteeing that the
constructs don't reach the nucleus. It is important not to use peptides
or other biomolecules for the construct to avoid that the cell cleave
the construct and let in the mutagen and the inhibitor, ultimately
poisoning itself.
the mutagen would affect the normal RNA populations of cells but it is
unlikely that such effects will be dire: some aging maybe but one that
would be transient (anomalous mRNAs and rRNAs, and anomalous proteins
from mutated mRNAs would be turned-over ultimately).
ideally the mutagen could have an antidote so that one is able to
neutralize it when it is not needed anymore, to give relief to
cytoplasmic mRNA and rRNA populations. One way is to choose one that
becomes inactive after it mutagenizes a base (nitrous acid?)
In any case the treatment with only the glycosylase-inhibitor construct
should not have any side effects since the enzyme is supposed to be
active only in the nucleus on nuclear DNA; and DNA, and even less native
DNA repair, should not be found in the cytoplasm.
simarly one could raise the mutation rate till right below the
saturation level of the glycosylase, but dosages maybe be hard to tune
best to you again
marcos
P.S. Besides: Has anybody tried to deliver an non-specific suicidal
ribonuclease/protease that would cleave once and then become inactive.
This would kill viroids but do hardly any lasting damage to cells
(especially the ribonuclease).
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