Novel antivirals and defective interfering particles

A hallmark of viruses is their high mutation rate and extraordinary adaptability. This poses a long-lasting challenge to the development of therapeutics. Any effective therapy quickly gives rise to so-called escape mutants of the virus, potentially resulting in treatment failure. A promising approach to circumvent the problem is a distinct class of gene therapy based on defective viruses. Currently, we focus on modeling and testing the evolution and transmission potential of this gene therapy for influenza viruses. The aim is to develop a conceptually new evolution-proof therapeutic approach that will sustainably control viral infection and/or purge viral population to collapse.

The current work builds upon the foundations of two of our previous works, where we show that 1) this gene therapy strategy can sustainably control viral infection by keeping up with viral evolution and 2) surprisingly, naturally occurring defective viruses can help the transmission of the functional virus, though the mechanisms are still unclear:

  1. Defective virus therapy for HIV infection

A long-standing challenge in efforts to control human immunodeficiency virus type 1 (HIV-1) is the rapid evolution of the virus. With Jamie Lloyd-Smith at UCLA, I analyzed the evolutionary properties of this class of HIV-1 gene therapies and showed that they are potentially robust to HIV-1 evolution, i.e. it can effectively and persistently reduce viral loads in HIV patients by keeping up with HIV-1 evolution.

TIP
Time course of the co-evolution between HIV-1 and therapeutical interfering particles

2. Transmission of defective dengue virus

The high deleterious mutation rate of RNA viruses ensures that many genomes are defective, and defective viruses have been observed in natural populations of many viruses. However, the long-term evolutionary and epidemiological consequences of the presence and transmission of defective viruses rarely have been discussed. My research at UCLA with Jamie Lloyd-Smith has partially focused on the evolution and spread of a lineage of defective dengue viruses. I (with John Aaskov, Eddie Holmes and Jamie Lloyd-Smith) analyzed the emergence and spread of a lineage of defective dengue viruses among populations, using a phylodynamic approach. We showed that, surprisingly, the co-transmission of this defective virus with the functional dengue virus has a higher transmission potential than the functional dengue virus alone, and that the spread of this lineage of defective viruses can potentially increase the overall dengue incidence substantially. This work shows that defective viruses can have powerful impact on viral evolution and emergence.

DengueDV
Phylogenetic tree of the emergence and spread of a defective dengue lineage (blue) and their functional partners (red).

 

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