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.