Strategies and efforts in circumventing the emergence of antiviral resistance against conventional antivirals

Figures

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  Fig. 1. Types of antivirals and their mechanisms of action. The various steps of the viral life cycle targeted by DAAs (purple) and HTAs (orange) are shown. A Viral binding inhibitors bind to viral glycoproteins, preventing them from binding host receptors, while host binding inhibitors act as host receptor antagonists, preventing their binding with viral glycoproteins required for viral entry. B Viral fusion inhibitors bind and disrupt the conformations of viral proteins responsible for mediating fusion between host and viral membranes. C Viral uncoating inhibitors bind to and interfere with viral proteins such as capsid or ion channels preventing capsid disassembly or endosomal acidification required for release of viral genome. D Viral nucleoside inhibitors bind to reverse transcriptases or polymerases and either cause chain termination or incorporation of a mutagen that drives a virus towards error catastrophe. E Host nucleotide depletion deprives viruses of purines and pyrimidines needed for genome replication. F Viral integrase strand transfer inhibitors bind to viral integrase active sites and displace viral DNA, preventing proviral incorporation into host genomes. G Host nuclear…

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  Fig. 2. Characteristics of RNA viruses and emergence of antiviral resistance. A Characteristics of RNA viruses that contribute to their high evolutionary rates and adaptability. B Comparison of direct and cross-resistance. Direct resistance is when a virus exposed to a single antiviral (Antiviral A) develops resistance to it. Cross-resistance is when a virus exposed to only one antiviral (Antiviral A) acquires mutations that confer resistance to it, as well as another antiviral (Antiviral B) to which the virus was not exposed. C Resistant mutants that confer a selective advantage over the wild type viruses in the presence of antivirals quickly become prevalent in the viral population. If these mutants are fitter than wild type even in the absence of antiviral, they are transmitted more often and becomes the dominant strain. Sustained transmission of these resistant viruses can render antivirals obsolete.

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  Fig. 3. Virus, host, and antiviral-associated factors that contribute to antiviral resistance. These different factors contribute to a suboptimal dose of antiviral being used during therapy, resulting in incomplete viral suppression which eventually leads to the emergence of antiviral resistance. A Virus-associated factors include reduced susceptibility to antivirals as a result of pre-treatment baseline resistance mutations, polymorphisms and variation in viral subtypes. B Host factors include genetic variation in hosts that affect their ability to respond to treatment or tolerate an antiviral. Various factors such as side effects, high pill burdens and frequent administration of antivirals contribute to poor adherence to antiviral regimens. C Antiviral factors include poor potency or the pharmacokinetic/pharmacodynamic profile of the antiviral that limits their effectiveness to suppress viruses. A low genetic barrier to resistance enables the viruses to gain resistance quickly.

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  Fig. 4. Fitness costs and compensatory mutations. A With multiple routes to develop resistance, both genetic barriers and fitness will determine which mutants will dominate. The higher the genetic barrier, the less likely resistance will emerge. Low genetic barrier and low fitness mutants (Mutant 1) are readily generated but selected against. Mutants with high fitness (Mutant 2), although unlikely to generate because of higher genetic barriers are likely to dominate the viral population if they emerge. Mutants with a very high genetic barrier (Mutant 3) are unlikely to appear because mutations incurring high fitness costs are required. B Resistance mutations confer a fitness advantage in the presence of an antiviral, but not in its absence. A double mutant with both resistance and compensatory mutations has better fitness than both wild type and resistant mutant alone in the presence of an antiviral, although not always in its absence. Compensatory mutations can occur stepwise with each compensatory mutant additively restoring the fitness lost by the resistance mutation. C Different mutations (Mutations A and B) work in synergy by conferring resistance to different antivirals (Antivirals…

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  Fig. 5. Combination therapy, pharmaco-enhancements and lethal mutagenesis. A The benefits of using antiviral combinations. Antiviral combinations can be used to exploit antagonistic resistance mutations which increase susceptibility to each other when they occur. Additionally, combinations lower doses of each constituent antiviral required for therapeutic effectiveness. Different antivirals (Antivirals A and B) also penetrate tissues to different degrees, which is especially important in pantropic viral infections. B Pharmaco-enhancements refer to modification of a drug to improve traits such as bioavailability and half-life. Boosting with a secondary antiviral (Antiviral B) slows the metabolism of the first antiviral (Antiviral A), prolonging exposure to the primary antiviral at the target site. C Mechanism of nucleotide analogue lethal mutagenesis. The analogue is incorporated into viral genomes during replication and increases the error rate of viral RNA-dependent RNA polymerase (RdRp), by allowing ambiguity in base pairing in subsequent rounds of replication, leading to an accumulation of erroneous mutations. Once the error rate exceeds the error threshold, fit viral genomes are no…

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  Fig. 6. Potential alternatives to conventional antivirals. Schematic depicting the general life cycle of a RNA or DNA virus, starting from viral attachment to release of new viruses (Steps 1 to 7). In RNA viruses, replication of their RNA genome occurs directly in the cytoplasm (Step 3a) whereas in DNA viruses, the DNA genome is first transported into the nucleus before being transcribed into mRNA (Step 3b). Figure shows the targets inhibited by each antiviral alternative, denoted by the red lines. A Monoclonal antibodies target the surface glycoproteins of viruses, preventing its binding to cell surface receptors and attachment of virus to the cell. B RNA interference is comprised mainly of siRNA and miRNA, each of which can be assembled with the RNA-induced silencing complex (RISC). siRNA associated with RISC induce gene silencing by targeting viral RNA from RNA virus genomes or the transcribed mRNA of DNA virus genomes. In contrast, miRNA associated with RISC repress the translation of RNA, thereby preventing the synthesis of any structural proteins required for the assembly of new viruses. C Defective viral genomes (DVGs) are typically present in RNA virus populations and bear…