Applied BiosafetyVol. 21, No. 3 Special FeaturesFree AccessCapsuleRobert A. RasmussenRobert A. RasmussenCorresponding Author: Robert A. Rasmussen, Wyss Institute for Biologically Inspired Engineering, 3 Blackfan Circle, Boston, MA 02215, USA. E-mail Address: robert.rasmussen@wyss.harvard.eduWyss Institute for Biologically Inspired Engineering, Boston, MA, USASearch for more papers by this authorPublished Online:1 Sep 2016AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail What’s new, what’s hot, what’s timely? If you don’t have time to search the Internet for the latest developments that might affect your work environment, you just might find some of that information in this Capsule column. Please email any comments, suggestions, or insights to Robert Rasmussen at robert.rasmussen@wyss.harvard.edu.Therapeutic Approaches to RNA Viruses That Exploit Their High Mutation RatesDue to their reliance on error-prone viral RNA polymerases for replication, RNA viruses exhibit very high rates of genetic mutation. Combined with selective pressure, these high mutation rates have imposed enormous difficulties in designing clinical treatments, as well as vaccines, against pathogenic RNA viruses because of the rapid emergence of drug-resistant and/or neutralizing antibody-resistant strains of RNA viruses. A recent review by Tanner et al1 describes 2 therapeutic approaches that in theory could be efficacious despite high rates of viral mutation. Neither approach is aimed at viral enzymes or receptors, the current targets for most antiretroviral therapies. Instead, they are aimed, either directly or indirectly, at structural viral components.The first approach is called dominant drug targeting through dominant-negative interactions, and the authors use the biology of viral capsid synthesis to demonstrate how the approach would operate. Viral capsids are polymerized intracellularly from whatever oligomeric precursors are available. When exposed to a drug that targets viral capsid precursors, selective pressure plus the continuous generation of viral RNA genome mutations can result in the formation of drug-resistant capsid precursor proteins. The result can be chimeric capsids composed of oligomeric precursor proteins encoded by both drug-sensitive and emergent drug-resistant genomes. Dominant-negative interactions occur during the assembling of both drug-resistant and drug-sensitive precursors into chimeric capsids because even if the capsid contains only a small minority of drug-sensitive proteins, the entire capsid and virus particle still remains drug sensitive. Proof-of-concept experiments for dominant drug targeting have already been successfully performed for both poliovirus and dengue virus infections.The second approach is based on exploiting the natural process of viral genetic interference. In any RNA virus-infected cell, error-prone RNA polymerase activity results in an intracellular mix of divergent viral RNA molecules. Genetic interference of the optimal replication kinetics of wild-type viruses occurs due to competition between wild-type and mutant viral genomes for a limited number of viral-packaging proteins as part of the encapsidation mechanism. To exploit genetic interference for treating RNA virus infections, a treatment approach would be to engineer so-called therapeutic infectious particles, or TIPs, containing interfering RNA to out-compete wild-type viruses. To have a competitive advantage, the number of intracellular genomic TIP RNA molecules must exceed the number of wild-type viral RNA molecules. By limiting the size of TIP RNA to encode only the necessary elements for efficient TIP genome replication and packaging, the length of TIP RNA is much shorter than wild-type viral genome RNA. For reasons that have to do either directly with their shorter length or with their higher affinity for certain RNA polymerases, shorter RNA genomes have a replication advantage over longer RNA genomes, thus ensuring that the number of TIP RNA molecules exceeds that of wild-type virus. This gives the relatively abundant TIP RNA genome a competitive stoichiometric advantage over the full-length RNA viral genome for being packaged, or “mobilized,” into the available virus-encoded capsids. As described using human immunodeficiency virus 1 (HIV-1) infection as a prototype for this approach, the authors suggest employing a lentiviral TIP to parasitize HIV-1 infected cells, with the lentiviral TIP genome essentially using HIV-1 as a packaging virus. Essentially, this controlled genetic interference via TIPS would keep replication of the original infecting RNA virus replication at low levels.Although using a lentiviral vector against HIV has been previously demonstrated (eg, using a lentiviral vector encoding a small hairpin RNA against HIV-1 env), the lentiviral vector was eventually lost over time. In contrast, the parasitic nature of using lentiviral TIPs against HIV-1 as described here would ensure that the therapeutic infectious particles remain as long as they are needed—that is, as long as there is HIV packaging. While no experimental data were shown using a potential TIP, in silico model analysis indicated the approach would be efficacious, and epidemiological models predict population infection prevalence would drop.Reference 1. Tanner E Kirkegaard K Weinberger L . Exploiting genetic interference for antiviral therapy. PLoS Genet. 2016;12(5):e1005986. Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Volume 21Issue 3Sep 2016 Information© ABSA International 2016To cite this article:Robert A. Rasmussen.Capsule.Applied Biosafety.Sep 2016.156-157.http://doi.org/10.1177/1535676016661773Published in Volume: 21 Issue 3: September 1, 2016PDF download
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