Dominant drug targets suppress the emergence of antiviral resistance

The emergence of drug resistance can defeat the successful treatment of pathogens that display high mutation rates, as exemplified by RNA viruses. Here we detail a new paradigm in which a single compound directed against a ‘dominant drug target’ suppresses the emergence of naturally occurring drug-resistant variants in mice and cultured cells. All new drug-resistant viruses arise during intracellular replication and initially express their phenotypes in the presence of drug-susceptible genomes. For the targets of most anti-viral compounds, the presence of these drug-susceptible viral genomes does not prevent the selection of drug resistance. Here we show that, for an inhibitor of the function of oligomeric capsid proteins of poliovirus, the expression of drug-susceptible genomes causes chimeric oligomers to form, thus rendering the drug-susceptible genomes dominant. The use of dominant drug targets should suppress drug resistance whenever multiple genomes arise in the same cell and express products in a common milieu. DOI: http://dx.doi.org/10.7554/eLife.03830.001
eLife digest Treating a viral infection with a drug sometimes has an unwanted side effect—the virus quickly becomes resistant to the drug. Viruses whose genetic information is encoded in molecules of RNA mutate faster than DNA viruses and are particularly good at developing resistance to drugs. This is because the process of copying the RNA is prone to errors, and by chance some of these errors, or mutations, may allow the virus to resist the drug's effects. Treating viral infections with most drugs destroys the viruses that are susceptible to the drug and inadvertently ‘selects’ for viruses that are resistant to the drug's effects. These drug-resistant viruses are harder to treat and often require physicians to switch between different drugs. Sometimes these new drug-resistant viruses spread and these new infections cannot be treated with drugs that would have worked in the past. So far, the best strategy to prevent drug-resistant viruses from growing in patients is to use multiple drugs, such as the life-saving treatments for HIV infection. However, for many viral infections—such as those that cause the common cold, dengue fever, Ebola, and polio—no drugs are yet available to treat infected people. Moreover, there are concerns that, if a new drug is used on its own, the viruses will quickly develop resistance to the drug and render it ineffective. Tanner et al. now show that an antiviral drug that interferes with the formation of the outer layer (or capsid) of the poliovirus inhibits the emergence of drug resistance. The drug, called V-073, is currently being tested as a treatment for poliovirus and will be useful in the worldwide eradication effort. Tanner et al. show that treating poliovirus-infected mice with V-073 does not select for drug-resistant strains of the virus—and provide evidence that this occurs because the drug targets an assemblage of proteins. The poliovirus capsid is assembled from a mix of proteins from different naturally occurring strains of the virus within the infected cell. A new strain of virus is always ‘born’ into a cell that is already infected by other viruses, which could be thought of as its parents, cousins and siblings. A new drug-resistant virus will therefore be forced to mix its capsid proteins with those of its ‘family’ members, who are all drug-sensitive. These hybrid capsids will remain vulnerable to the drug—and in this way, the resistant strains do not become the dominant form of the virus. Tanner et al. also discovered a way to screen for drugs that have a similar resistance-blocking effect. These drugs would target capsids, or other viral structures made up of a mix of proteins from different virus strains. Such drugs might be useful against other viruses including the ones that cause the common cold, hepatitis C, or dengue fever. DOI: http://dx.doi.org/10.7554/eLife.03830.002