Design Requirements for Interfering Particles To Maintain Coadaptive Stability with HIV-1

Abstract

Defective interfering particles (DIPs) are viral deletion mutants lacking essential transacting or packaging elements and must be complemented by wild-type virus to propagate. DIPs transmit through human populations, replicating at the expense of the wild-type virus and acting as molecular parasites of viruses. Consequently, engineered DIPs have been proposed as therapies for a number of diseases, including human immunodeficiency virus (HIV). However, it is not clear if DIP-based therapies would face evolutionary blocks given the high mutation rates and high within-host diversity of lentiviruses. Divergent evolution of HIV and DIPs appears likely since natural DIPs have not been detected for lentiviruses, despite extensive sequencing of HIVs and simian immunodeficiency viruses (SIVs). Here, we tested if the apparent lack of lentiviral DIPs is due to natural selection and analyzed which molecular characteristics a DIP or DIP-based therapy would need to maintain coadaptive stability with HIV-1. Using a well-established mathematical model of HIV-1 in a host extended to include its replication in a single cell and interference from DIP, we calculated evolutionary selection coefficients. The analysis predicts that interference by codimerization between DIPs and HIV-1 genomes is evolutionarily unstable, indicating that recombination between DIPs and HIV-1 would be selected against. In contrast, DIPs that interfere via competition for capsids have the potential to be evolutionarily stable if the capsid-to-genome production ratio of HIV-1 is >1. Thus, HIV-1 variants that attempt to "starve" DIPs to escape interference would be selected against. In summary, the analysis suggests specific experimental measurements that could address the apparent lack of naturally occurring lentiviral DIPs and specifies how therapeutic approaches based on engineered DIPs could be evolutionarily robust and avoid recombination.

Continuous Influenza Virus Production in Cell Culture Shows a Periodic Accumulation of Defective Interfering Particles

“…The generation of DIPs is a common phenomenon for different viruses [29] that may be difficult to control. However, the lack of lentiviral DIPs has been reported [30] and host cell factors have been described to be involved in the de novo generation or replication of DI genomes [31]–[33]. Consequently, further research is needed to elucidate which viral and host cell properties would enable the establishment of continuous virus production processes.…”

Reply to “Coadaptive Stability of Interfering Particles with HIV-1 When There Is an Evolutionary Conflict”

“…Ke and Lloyd-Smith for their letter (1) highlighting the critical discrepancies between the claims of their recent simulation study (2) and the results derived by evolutionary calculations in our analytic study (3). In contrast to our direct calculations, Ke and Lloyd-Smith argue that therapeutic interfering particles (TIPs)-generated by conditionally replicating vectors-would stably cross dimerize with HIV and indefinitely coevolve with the virus.…”

“…In contrast, our analysis (3) shows that the capsid-stealing mechanism maintains coevolutionary stability and is as a robust strategy for designing potentially lifelong anti-HIV therapies.…”

The evolutionary ecology of molecular replicators

“…On this view, the coviruses of plants and amoeba-dwelling entities like Sputnik Virophage, for example, are the norm. Accepting this allows the study of the evolution of molecular replicators to proceed unencumbered by the taxonomic affiliations of the environments they may be gaming in, to address more challenging phenomena like limitations on the numbers of covirus partners [36], threshold phenomena and ‘catastrophes’ in the evolution of coviruses [30] and difficulties in the design of HIV DIs [37]. …”