Design requirements for interfering particles to maintain coadaptive stability with HIV-1

Area of Science:

• Virology
• Evolutionary Biology
• Computational Biology

Background:

• Defective interfering particles (DIPs) are viral mutants that parasitize wild-type viruses.
• Engineered DIPs are explored as potential therapies for diseases like HIV.
• Lentiviruses, such as HIV, exhibit high mutation rates and within-host diversity, raising questions about DIP therapy efficacy.

Purpose of the Study:

• To investigate the evolutionary stability of DIPs in the context of HIV-1.
• To identify molecular characteristics required for coadaptive stability between HIV-1 and DIPs.
• To assess potential evolutionary hurdles for DIP-based HIV therapies.

Main Methods:

• Utilized a mathematical model simulating HIV-1 replication within a host, including DIP interference.
• Calculated evolutionary selection coefficients to predict the stability of different DIP interference mechanisms.
• Analyzed the impact of capsid competition and genome codimerization on evolutionary dynamics.

Main Results:

• Interference via genome codimerization between DIPs and HIV-1 is predicted to be evolutionarily unstable, with selection against recombination.
• DIPs interfering through competition for capsids demonstrate potential for evolutionary stability if the HIV-1 capsid-to-genome ratio exceeds 1.
• HIV-1 variants attempting to evade interference by starving DIPs are predicted to be selected against.

Conclusions:

• The study provides insights into the apparent absence of natural lentiviral DIPs.
• It suggests that engineered DIPs interfering via capsid competition could be evolutionarily robust for HIV therapy.
• The findings guide experimental approaches to validate these predictions and refine therapeutic strategies.