Author response: Transmission genetics of drug-resistant hepatitis C virus

Viruses are simple organisms that consist of genetic information and a few types of proteins. They cannot replicate on their own, and instead hijack the molecular machinery of a host cell to produce more of themselves. Inside an infected cell, the genetic information of the virus is replicated and ‘read’ to create viral proteins. These components are then assembled to form a new generation of viruses. During this process, genetic errors may occur that lead to modifications in the viral proteins, and help the virus become resistant to treatment. For instance, a viral protein that used to be targeted by a drug can change slightly and not be recognized anymore. Currently, the most efficient way to fight drug resistance is to use combination therapy, where several drugs are given at the same time. This strategy is successful, for example to treat infections with the hepatitis C virus, but it is also expensive, especially for developing countries. An alternative approach is dominant-drug targeting, which exploits the fact that both drug-resistant and drug-susceptible viruses are ‘born’ in the same cell. There, the susceptible viruses can overwhelm and ‘mask’ the benefits of the resistant ones. For example, proteins from resistant strains, which are no longer detected by a treatment, can bind to proteins from susceptible viruses; drugs will still be able to recognize these resulting viral structures. The proteins that operate in such ways are potential dominant-drug targets. However, resistant and susceptible strains can also cohabit without any contacts if their proteins do not interact with each other. Now, van Buuren et al. screen several viral proteins, including one called NS5A, to test whether a dominant drug target exists for the hepatitis C virus. Only a few molecules of a drug that targets NS5A can stop the virus from growing. In theory, drug-bound NS5A proteins could block their non-drug-bound neighbors, but when these drugs have been used on their own, resistance quickly emerged. Experiments showed that NS5A is not a dominant drug target because the drug-resistant and drug-susceptible proteins do not mix. Unless ‘forced’ in the laboratory, NS5A proteins only bind to the ones produced by the same strain of virus. This explains why resistant viruses quickly take over when NS5A drugs are the sole treatment. However, other hepatitis C proteins, such as the HCV core protein, are known to mix during the assembly of the virus, and thus are likely be dominant drug targets.

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