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.