Unveil critical mutations responsible for antiviral drug
resistance, contributing to precision medicine
Previously Jabara and colleagues have employed molecular barcodes to
create a consensus sequence for individual viral templates amplified
from HIV-1infected individuals and sought for the emergence of multiple
single-nucleotide polymorphisms (SNPs) responsible for
drug-resistance[17].
In such a way only SNPs present in the time as materials were collected
can be identified; whether these SNPs have been present from the
beginning of the primary infection or they were the SNPs derived from
several rounds of nucleotide substitutions over the period of the
treatment is however not traceable. Indeed, some substituted nucleotides
in virus sequences may not be essential for the final phenotype and
could be replaced due to the effects from different constraints during
the selection process. A genotype-traceable model for monitoring the
dynamics of virus sequence changes is thus important to recapitulate
evolutionary trajectories at a single-sequence level.
Our idea is that, by using barcoded viruses to infect host cells present
in the selection pressure of antiviral drugs, after several rounds of
passages we will then look for the variants that emerge mutations,
rendering the viruses capable of surviving in the presence of antiviral
drugs. Similar ideas have been applied on mosquito Infection models used
to recapitulate the emerging variant of chikungunya virus that occurred
in the Indian Ocean
islands[152].
At that stage, molecular barcodes, accompanying high-throughput
sequencing, allow us to segregate every dominant variant at a
single-sequence level and decode corresponding genotypes. This approach
can be done with different sorts of combinations of antiviral drugs to
build up a database, which systematically associates different antiviral
drug-resistant variants with corresponding mutations. Since viruses used
in this approach are barcoded, we can also construct phylogenetic trees
for individual antiviral drug-resistant variants, allowing us to monitor
whether or not any intermediate nucleotide substitutions are required
during the course of the evolutionary process to result in final
antiviral drugs-resistant phenotypes. If this is the case, such
information could be used as a guideline for clinical diagnostics. In
other words, after unveiling the genotypes of viruses present in
patients, based on experimental outputs released from this
genotype-traceable model, medical doctors can foresee that an indicated
patient might exhibit antiviral drug tolerance to certain drugs and
adjust antiviral regimens for treatments to satisfy the need for every
individual.