Exploiting Genetic Interference for Antiviral Therapy

Abstract

Rapidly evolving viruses are a major threat to human health. Such viruses are often highly pathogenic (e.g., influenza virus, HIV, Ebola virus) and routinely circumvent therapeutic intervention through mutational escape. Error-prone genome replication generates heterogeneous viral populations that rapidly adapt to new selection pressures, leading to resistance that emerges with treatment. However, population heterogeneity bears a cost: when multiple viral variants replicate within a cell, they can potentially interfere with each other, lowering viral fitness. This genetic interference can be exploited for antiviral strategies, either by taking advantage of a virus's inherent genetic diversity or through generating de novo interference by engineering a competing genome. Here, we discuss two such antiviral strategies, dominant drug targeting and therapeutic interfering particles. Both strategies harness the power of genetic interference to surmount two particularly vexing obstacles-the evolution of drug resistance and targeting therapy to high-risk populations-both of which impede treatment in resource-poor settings.

Fig 1. Schematic of targets of genetic interference: capsid assembly and genome encapsidation.

Individual capsid subunits (yellow triangles) assemble into pentamers, which assemble to form the full icosahedral capsid. The viral genome (blue) is packaged into the capsid.

Fig 2. Exploiting genetic interference in capsid assembly and encapsidation for antiviral therapy.

(A) Dominant drug targeting. Drug-resistant genomes (red curves) arise from wild-type genomes (gray curves) during replication within an infected cell. Drug-resistant and drug-sensitive genomes generate capsid proteins (red and gray triangles, respectively), which assemble into chimeric capsids. The drug (orange triangle) interferes with the function of both wild-type and chimeric capsids. (B) Therapeutic interfering particles (TIPs). After reverse transcription and integration, the HIV-1 proviral genome (red line) is integrated within the host genome and generates cytoplasmic mRNAs (red curves) by using its trans elements Tat and Rev as well as host cofactors. These mRNAs translate viral proteins, including capsid (red), and some of the mRNAs also serve as genomic RNA and are encapsidated in diploid form. TIP genomes (blue line) carry large deletions but are also reverse transcribed and integrated into the host genome. TIPs also utilize wild-type HIV-1 trans elements (e.g., Tat and Rev) to express genomic RNAs in the cytoplasm (blue curves). Since they have extensive deletions, these RNAs encode few if any proteins but are transcribed in higher proportions than wild-type RNAs. Because they are present at higher concentrations, TIP RNAs can outcompete wild-type virus (red) for packaging proteins and encapsidate their own diploid genomes in place of HIV-1 genomes.