Evolutionarily Stable Attenuation by Genome Rearrangement in a Virus

Cecchini, Nicole; Schmerer, Matthew; Molineux, Ian J.; Springman, Rachael; Bull, James J.

doi:10.1534/g3.113.006403

Cited by 19 publications

(23 citation statements)

References 35 publications

(65 reference statements)

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“…Rearrangement of viral genomes has recently been explored to generate attenuated viruses exhibiting properties amenable to the development of live attenuated vaccines, including DNA (37,64), double-stranded RNA (dsRNA) (38), and positive-stranded (39) and negative-stranded (40-45, 65, 66) RNA viruses. However, similar viral genome reorganization has not yet been explored for the development of arenavirus vaccines.…”

Section: Discussionmentioning

confidence: 99%

Arenavirus Genome Rearrangement for the Development of Live Attenuated Vaccines

Cheng

Ortiz-Riaño

Torre

et al. 2015

J Virol

100

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Several members of the Arenaviridae family cause hemorrhagic fever disease in humans and pose serious public health problems in their geographic regions of endemicity as well as a credible biodefense threat. To date, there have been no FDA-approved arenavirus vaccines, and current antiarenaviral therapy is limited to an off-label use of ribavirin that is only partially effective. Arenaviruses are enveloped viruses with a bisegmented negative-stranded RNA genome. Each genome segment uses an ambisense coding strategy to direct the synthesis of two viral polypeptides in opposite orientations, separated by a noncoding intergenic region. Here we have used minigenome-based approaches to evaluate expression levels of reporter genes from the nucleoprotein (NP) and glycoprotein precursor (GPC) loci within the S segment of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). We found that reporter genes are expressed to higher levels from the NP than from the GPC locus. Differences in reporter gene expression levels from the NP and GPC loci were confirmed with recombinant trisegmented LCM viruses. We then used reverse genetics to rescue a recombinant LCMV ( A renaviruses are enveloped viruses with a bisegmented negative-strand (NS) RNA genome that cause chronic infections of rodents across the world (1). Zoonotic transmission through either direct contact with contaminated material or inhalation of aerosolized particles can result in severe infection in humans (1). Several arenaviruses, mainly, Lassa virus (LASV), the agent responsible for Lassa fever (LF) in western Africa, and Junín virus (JUNV), the causative agent of Argentine hemorrhagic fever (AHF) in the Argentinean Pampas, cause severe HF diseases in humans that are associated with high morbidity and significant mortality, posing important health problems in their regions of endemicity (1-3). Importantly, increased travel has resulted in the importation of LF into nonendemic metropolitan regions around the globe, including the United States (4, 5), Europe (6), and Japan (7). Moreover, similarly to the situation recently illustrated with the 2014 Ebola virus outbreak in western Africa (8, 9), evidence indicates that regions of LASV endemicity are expanding. In addition, the recent identification of two novel HF-causing arenaviruses, Chapare virus in Bolivia (10) and Lujo virus in South Africa (11), has further reinforced concerns about the emergence of novel HF-causing arenaviruses. Additionally, evidence indicates that the lymphocytic choriomeningitis virus (LCMV) prototypic arenavirus, distributed worldwide, is a neglected human pathogen of clinical significance (12-15). Besides their impact in human public health, arenaviruses pose also a credible biodefense threat, and six of them, including LCMV, LASV, and JUNV, are classified as NIAID category A agents (2, 16). Threats posed by humanpathogenic arenaviruses are further aggravated by the lack of FDA-approved vaccines (1) and by current antiarenaviral therapy

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Section: Discussionmentioning

confidence: 99%

Arenavirus Genome Rearrangement for the Development of Live Attenuated Vaccines

Cheng

Ortiz-Riaño

Torre

et al. 2015

J Virol

100

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“…Importantly, the gene rearrangements described in the current study are unlikely to occur in nature, due to the replication mechanism and low recombination rate of viruses in Mononegavirales ( Han and Worobey, 2011 ). In bacteriophage, genome rearrangement and subsequent evolution diminished the ability of the virus to adapt to new environments ( Cecchini et al, 2013 ). We predicted that genomic reorganization in VSV should hinder the ability for the virus to adapt in a novel cellular environment, relative to wild type VSV.…”

Section: Introductionmentioning

confidence: 99%

Genome rearrangement affects RNA virus adaptability on prostate cancer cells

et al. 2015

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Gene order is often highly conserved within taxonomic groups, such that organisms with rearranged genomes tend to be less fit than wild type gene orders, and suggesting natural selection favors genome architectures that maximize fitness. But it is unclear whether rearranged genomes hinder adaptability: capacity to evolutionarily improve in a new environment. Negative-sense non-segmented RNA viruses (order Mononegavirales) have specific genome architecture: 3′ UTR – core protein genes – envelope protein genes – RNA-dependent RNA-polymerase gene – 5′ UTR. To test how genome architecture affects RNA virus evolution, we examined vesicular stomatitis virus (VSV) variants with the nucleocapsid (N) gene moved sequentially downstream in the genome. Because RNA polymerase stuttering in VSV replication causes greater mRNA production in upstream genes, N gene translocation toward the 5′ end leads to stepwise decreases in N transcription, viral replication and progeny production, and also impacts the activation of type 1 interferon mediated antiviral responses. We evolved VSV gene-order variants in two prostate cancer cell lines: LNCap cells deficient in innate immune response to viral infection, and PC-3 cells that mount an IFN stimulated anti-viral response to infection. We observed that gene order affects phenotypic adaptability (reproductive growth; viral suppression of immune function), especially on PC-3 cells that strongly select against virus infection. Overall, populations derived from the least-fit ancestor (most-altered N position architecture) adapted fastest, consistent with theory predicting populations with low initial fitness should improve faster in evolutionary time. Also, we observed correlated responses to selection, where viruses improved across both hosts, rather than suffer fitness trade-offs on unselected hosts. Whole genomics revealed multiple mutations in evolved variants, some of which were conserved across selective environments for a given gene order.

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“…They need to be designed to elicit protection while minimizing the chances that they evolve to be harmful after being administered to a patient. By engineering viruses with genome rearrangements or deletions of nonessential but useful regions, it has been possible to not only lower initial fitness [22,23] but also to limit the fitness they attain on sustained adaptation [22,24]. These genomes will typically evolve a fitness above their starting value, but they cannot catch up with wild type.…”

Section: Engineering Fitness Landscapes To Suppress Evolutionmentioning

confidence: 99%

“…On extended adaptation, the engineered genomes do not re-establish the wild-type gene order. Partial evolutionary reversion is possible, but it falls short of returning to wild-type levels [24,67]. …”

Section: Engineering Fitness Landscapes To Suppress Evolutionmentioning

confidence: 99%

Arresting Evolution

Bull

Barrick

2017

Trends in Genetics

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Evolution in the form of selective breeding has long been harnessed as a useful tool by humans. However, rapid evolution can also be a danger to our health and a stumbling block for biotechnology. Unwanted evolution can underlie the emergence of drug and pesticide resistance, cancer, and weeds. It makes live vaccines and engineered cells inherently unreliable and unpredictable, and therefore potentially unsafe. Yet, there are strategies that have been and can possibly be used to stop or slow many types of evolution. We review and classify existing population genetics-inspired methods for arresting evolution. Then, we discuss how genome editing techniques enable a radically new set of approaches to limit evolution.

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Evolutionarily Stable Attenuation by Genome Rearrangement in a Virus

Cited by 19 publications

References 35 publications

Arenavirus Genome Rearrangement for the Development of Live Attenuated Vaccines

Arenavirus Genome Rearrangement for the Development of Live Attenuated Vaccines

Genome rearrangement affects RNA virus adaptability on prostate cancer cells

Arresting Evolution

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