Evolution of Drug Resistance: Viruses

Please contact Roland Regös if you want to choose a paper within this topic.

Bonhoeffer, S., and M. A. Nowak. 1997. Pre-existence and emergence of drug resistance in HIV-1 infection. Proceedings of the Royal Society of London Series B-Biological Sciences 264:631-637. [pdf]
Antiviral treatment of HIV-1 infection often fails because of the rapid emergence of resistant virus within weeks of the start of therapy. This raises the question of whether resistant viruses pre-exist in drug-naive patients or whether it is produced after the start of therapy. Here we compare the likelihood of pre-existence with the likelihood of production of resistant virus during therapy. We show that provided resistant virus pre-exists, then a stronger therapy may lead to a greater initial reduction of virus load, but will also cause a faster rise of resistant virus. In this case the total benefit of treatment is independent of the degree of inhibition of sensitive virus. If, on the other hand, resistant mutants do not pre-exist, then the emergence of resistance during treatment depends on the efficacy of the drug. If the drug is sufficiently potent to eradicate sensitive virus, then the probability that resistant mutants first appear during therapy is smaller than the probability that they existed before therapy. If the drug cannot eradicate the sensitive virus, then after sufficiently long time, resistant mutants will appear. However, mutants that are unlikely to pre-exist may take a long time to appear.

Bretscher, M. T., C. L. Althaus, V. Muller, and S. Bonhoeffer. 2004. Recombination in HIV and the evolution of drug resistance: for better or for worse? Bioessays 26:180-188. [pdf]
The rapid evolution of drug resistance remains a major obstacle for HIV therapy. The capacity of the virus for recombination is widely believed to facilitate the evolution of drug resistance. Here, we challenge this intuitive view. We develop a population genetic model of HIV replication that incorporates the processes of mutation, cellular superinfection, and recombination. We show that cellular superinfection increases the abundance of low fitness viruses at the expense of the fittest strains due to the mixing of viral proteins during virion assembly. Moreover, we argue that whether recombination facilitates the evolution of drug resistance depends critically on how resistance mutations interact to determine viral fitness. Contrary to the commonly held belief, we find that, under the most plausible biological assumptions, recombination is expected to slow down the rate of evolution of multi-drug-resistant virus during therapy.

Fraser, C. 2005. HIV recombination: what is the impact on antiretroviral therapy? Journal of the Royal Society Interface 2:489-503. [pdf]
Retroviral recombination is a potential mechanism for the development of multiply drug resistant viral strains but the impact on the clinical outcomes of antiretroviral therapy in HIV-infected patients is unclear. Recombination can favour resistance by combining single-point mutations into a multiply resistant genome but can also hinder resistance by breaking up associations between Mutations. Previous analyses, based on population genetic models, have suggested that whether recombination is favoured or hindered depends on the fitness interactions between loci, or epistasis. In this paper, a mathematical model is developed that includes viral dynamics during therapy and shows that population dynamics interact nontrivially with population genetics. The outcome of therapy depends critically on the changes to the frequency of cell co-infection and I review the evidence available.,Where recombination does have an effect on therapy, it is always to slow or even halt the emergence of multiply resistant strains. I also find that for patients newly infected with multiply resistant strains, recombination can act to prevent reversion to wild-type virus. The analysis suggests that treatment targeted at multiple parts of the viral life-cycle may be less prone to drug resistance due to the genetic barrier caused by recombination but that, once selected, mutants resistant to such regimens may be better able to persist in the population.

Nelson, M. I., L. Simonsen, C. Viboud, M. A. Miller, and E. C. Holmes. 2009. The origin and global emergence of adamantane resistant A/H3N2 influenza viruses. Virology 388:270-278. [pdf]
Resistance to the adamantane class of antiviral drugs by human A/H3N2 influenza viruses currently exceeds 90% in the United States and multiple Asian countries. Adamantane resistance is associated with a single amino acid change (S31N) in the M2 protein, which was shown to rapidly disseminate globally in 2005 in association with a genome reassortment event. However, the exact origin of influenza A/H3N2 viruses carrying the S31N mutation has not been characterized, particularly in South-East Asia. We therefore conducted a phylogenetic analysis of the HA, NA, and M1/2 segments of viral isolates collected between 1997 and 2007 from temperate localities in the Northern hemisphere (New York State, United States, 492 isolates) and Southern hemisphere (New Zealand and Australia, 629 isolates) and a subtropical locality in South-East Asia (Hong Kong, 281 isolates). We find that although the S31N mutation was independently introduced at least 11 times, the vast majority of resistant viruses now circulating globally descend from a single introduction that was first detected in the summer of 2003 in Hong Kong. These resistant viruses were continually detected in Hong Kong throughout 2003-2005, acquired a novel HA through reassortment during the first part of 2005, and thereafter spread globally. The emergence and persistence of adamantane resistant viruses in Hong Kong further supports a source-sink model of global influenza virus ecology, in which South-East Asia experiences continuous viral activity and repeatedly seeds epidemics in temperate areas. (c) 2009 Elsevier Inc. All rights reserved.

Pfeiffer, J. K., and K. Kirkegaard. 2003. A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity. Proceedings of the National Academy of Sciences of the United States of America 100:7289-7294. [pdf]
Ribavirin is a nucleotide analog that can be incorporated by viral polymerases, causing mutations by allowing base mismatches. It is currently used therapeutically as an antiviral drug during hepatitis C virus infections. During the amplification of poliovirus genomic RNA or hepatitis C replicons, error frequency is known to increase upon ribavirin treatment. This observation has led to the hypothesis that ribavirin's antiviral activity results from error catastrophe caused by increased mutagenesis of viral genomes. Here, we describe the generation of ribavirin-resistant poliovirus by serial viral passage in the presence of increasing concentrations of the drug. Ribavirin resistance can be caused by a single amino acid change, G64S, in the viral polymerase in an unresolved portion of the fingers domain. Compared with wild-type virus, ribavirin-resistant poliovirus displays increased fidelity of RNA synthesis in the absence of ribavirin and increased survival both in the presence of ribavirin and another mutagen, 5-azacytidine. Ribavirin-resistant poliovirus represents an unusual class of viral drug resistance: resistance to a mutagen through increased fidelity.

Regoes, R. R., and S. Bonhoeffer. 2006. Emergence of drug-resistant influenza virus: Population dynamical considerations. Science 312:389-391. [pdf]
Given the considerable challenges to the rapid development of an effective vaccine against influenza, antiviral agents wilt play an important role as a first-tine defense if a new pandemic occurs. The large-scale use of drugs for chemoprophylaxis and treatment wilt impose strong selection for the evolution of drug-resistant strains. The ensuing transmission of those strains could substantially limit the effectiveness of the drugs as a first-tine defense. Summarizing recent data on the rate at which the treatment of influenza infection generates resistance de novo and on the transmission fitness of resistant virus, we discuss possible implications for the epidemiological spread of drug resistance in the context of an established population dynamic model.

Wu, J. T., G. M. Leung, M. Lipsitch, B. S. Cooper, and S. Riley. 2009. Hedging against Antiviral Resistance during the Next Influenza Pandemic Using Small Stockpiles of an Alternative Chemotherapy. Plos Medicine 6. [pdf]
Background: The effectiveness of single-drug antiviral interventions to reduce morbidity and mortality during the next influenza pandemic will be substantially weakened if transmissible strains emerge which are resistant to the stockpiled antiviral drugs. We developed a mathematical model to test the hypothesis that a small stockpile of a secondary antiviral drug could be used to mitigate the adverse consequences of the emergence of resistant strains. Methods and Findings: We used a multistrain stochastic transmission model of influenza to show that the spread of antiviral resistance can be significantly reduced by deploying a small stockpile (1% population coverage) of a secondary drug during the early phase of local epidemics. We considered two strategies for the use of the secondary stockpile: early combination chemotherapy (ECC; individuals are treated with both drugs in combination while both are available); and sequential multidrug chemotherapy (SMC; individuals are treated only with the secondary drug until it is exhausted, then treated with the primary drug). We investigated all potentially important regions of unknown parameter space and found that both ECC and SMC reduced the cumulative attack rate (AR) and the resistant attack rate (RAR) unless the probability of emergence of resistance to the primary drug p(A) was so low (less than 1 in 10,000) that resistance was unlikely to be a problem or so high (more than 1 in 20) that resistance emerged as soon as primary drug monotherapy began. For example, when the basic reproductive number was 1.8 and 40% of symptomatic individuals were treated with antivirals, AR and RAR were 67% and 38% under monotherapy if p(A) = 0.01. If the probability of resistance emergence for the secondary drug was also 0.01, then SMC reduced AR and RAR to 57% and 2%. The effectiveness of ECC was similar if combination chemotherapy reduced the probabilities of resistance emergence by at least ten times. We extended our model using travel data between 105 large cities to investigate the robustness of these resistance-limiting strategies at a global scale. We found that as long as populations that were the main source of resistant strains employed these strategies (SMC or ECC), then those same strategies were also effective for populations far from the source even when some intermediate populations failed to control resistance. In essence, through the existence of many wild-type epidemics, the interconnectedness of the global network dampened the international spread of resistant strains. Conclusions: Our results indicate that the augmentation of existing stockpiles of a single anti-influenza drug with smaller stockpiles of a second drug could be an effective and inexpensive epidemiological hedge against antiviral resistance if either SMC or ECC were used. Choosing between these strategies will require additional empirical studies. Specifically, the choice will depend on the safety of combination therapy and the synergistic effect of one antiviral in suppressing the emergence of resistance to the other antiviral when both are taken in combination.

Gerrish, P.J., and GarcÌa-Lerma, J.G. 2003. Mutation rate and the efficacy of antimicrobial drug treatment. Lancet Infectious Diseases 3:28-32. [pdf]
Despite rapid progress in drug development, microbial infections in general are becoming increasingly difficult to treat as a result of the emergence of drug-resistant strains. In some cases, such as HIV-1, the early goal of eradicating infections with antimicrobial drugs is, for now, being replaced with the more pragmatic goal of controlling infections over long periods of time through a succession of transiently effective treatments. Because treatment efficacy is often incomplete, studying the degree of treatment efficacy has great relevance to clinical disease management. We derived a model describing the association between the mutation rate of the pathogen and the degree of treatment efficacy. We found that drug treatment is most effective when the mutation rate of the pathogen is either very low or, perhaps counterintuitively, very high. We discuss this finding in the light of a promising new treatment strategy for RNA viruses that combines antiviral compounds with a mutagen.