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.
