Dataset Information

Harnessing host-virus evolution in antiviral therapy and immunotherapy.

ABSTRACT: Pathogen resistance and development costs are major challenges in current approaches to antiviral therapy. The high error rate of RNA synthesis and reverse-transcription confers genome plasticity, enabling the remarkable adaptability of RNA viruses to antiviral intervention. However, this property is coupled to fundamental constraints including limits on the size of information available to manipulate complex hosts into supporting viral replication. Accordingly, RNA viruses employ various means to extract maximum utility from their informationally limited genomes that, correspondingly, may be leveraged for effective host-oriented therapies. Host-oriented approaches are becoming increasingly feasible because of increased availability of bioactive compounds and recent advances in immunotherapy and precision medicine, particularly genome editing, targeted delivery methods and RNAi. In turn, one driving force behind these innovations is the increasingly detailed understanding of evolutionarily diverse host-virus interactions, which is the key concern of an emerging field, neo-virology. This review examines biotechnological solutions to disease and other sustainability issues of our time that leverage the properties of RNA and DNA viruses as developed through co-evolution with their hosts.

SUBMITTER: Heaton SM

PROVIDER: S-EPMC6613463 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Harnessing host-virus evolution in antiviral therapy and immunotherapy.

Heaton Steven M SM

Clinical & translational immunology 20190708 7

Pathogen resistance and development costs are major challenges in current approaches to antiviral therapy. The high error rate of RNA synthesis and reverse-transcription confers genome plasticity, enabling the remarkable adaptability of RNA viruses to antiviral intervention. However, this property is coupled to fundamental constraints including limits on the size of information available to manipulate complex hosts into supporting viral replication. Accordingly, RNA viruses employ various means ...[more]

PMID: 31312450

Similar Datasets

Project description:UnlabelledThe host-targeted antiviral drug UV-4B reduces viral replication and promotes survival in a mouse model of experimental dengue virus (DENV) infection. UV-4B is an iminosugar that inhibits the α-glucosidase family of enzymes and subsequently the folding of glycosylated proteins, both viral and host. Here, we utilized next-generation sequencing to investigate evolution of a flavivirus under selective pressure by a host-targeted antiviral in vivo. In viral populations recovered from UV-4B-treated mice, there was a significant increase in the number of single-nucleotide polymorphisms (SNPs) and the ratio of nonsynonymous to synonymous SNPs compared to findings in viral populations from vehicle-treated mice. The strongest evidence of positive selection was in the glycosylated membrane protein, thereby providing in vivo validation of the mechanism of action of an iminosugar. In addition, mutations in glycosylated proteins were present only in drug-treated mice after a single passage. However, the bulk of the other mutations were present in both populations, indicating nonspecific selective pressure. Together with the continued control of viremia by UV-4B, these findings are consistent with the previously predicted high genetic barrier to escape mutations in host-targeted antivirals.ImportanceAlthough hundreds of millions of people are infected with DENV every year, there is currently no approved vaccine or antiviral therapy. UV-4B has demonstrated antiviral activity against DENV and is expected to enter clinical trials soon. Therefore, it is important to understand the mechanisms of DENV resistance to UV-4B. Host-targeted antivirals are thought to have a higher genetic barrier to escape mutants than directly acting antivirals, yet there are very few published studies of viral evolution under host-targeted antivirals. No study to date has described flavivirus evolution in vivo under selective pressure by a host-based antiviral drug. We present the first in vivo study of the sequential progression of viral evolution under selective pressure by a host-targeted antiviral compound. This study bolsters support for the clinical development of UV-4B as an antiviral drug against DENV, and it provides a framework to compare how treatment with other host-targeted antiflaviviral drugs in humans and different animal models influence viral genetic diversity.

Project description:Pegylated interferon plus ribavirin therapy for hepatitis C virus (HCV) fails in approximately half of genotype 1 patients. Treatment failure occurs either by nonresponse (minimal declines in viral titer) or relapse (robust initial responses followed by rebounds of viral titers during or after therapy). HCV is highly variable genetically. To determine if viral genetic differences contribute to the difference between response and relapse, we examined the inter-patient genetic diversity and mutation pattern in the full open reading frame HCV genotype 1a consensus sequences.Pre- and post-therapy sequences were analyzed for 10 nonresponders and 10 relapsers from the Virahep-C clinical study. Pre-therapy interpatient diversity among the relapsers was higher than in the nonresponders in the viral NS2 and NS3 genes, and post-therapy diversity was higher in the relapsers for most of HCV's ten genes. Pre-therapy diversity among the relapsers was intermediate between that of the non-responders and responders to therapy. The average mutation rate was just 0.9% at the amino acid level and similar numbers of mutations occurred in the nonresponder and relapser sequences, but the mutations in NS2 of relapsers were less conservative than in nonresponders. Finally, the number and distribution of regions under positive selection was similar between the two groups, although the nonresponders had more foci of positive selection in E2.The HCV sequences were unexpectedly stable during failed antiviral therapy, both nonresponder and relapser sequences were under selective pressure during therapy, and variation in NS2 may have contributed to the difference in response between the nonresponder and relapser groups. These data support a role for viral genetic variability in determining the outcome of anti-HCV therapy, with those sequences that are more distant from an optimal sequence being less able to resist the pressures of interferon-based therapy.ClinicalTrials.gov NCT00038974.

Dataset Information

Harnessing host-virus evolution in antiviral therapy and immunotherapy.

Publications

Harnessing host-virus evolution in antiviral therapy and immunotherapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets