Discovery and Engineering of a Therapeutic Interfering Particle (TIP): a combination self-renewing antiviral

@article{Tanner2019DiscoveryAE,
  title={Discovery and Engineering of a Therapeutic Interfering Particle (TIP): a combination self-renewing antiviral},
  author={Elizabeth J Tanner and Seung-yong Jung and Joshua J. Glazier and Cassandra E. Thompson and Yuqi Zhou and Benjamin Martin and Hye-In Son and James L. Riley and Leor S. Weinberger},
  journal={bioRxiv},
  year={2019}
}
Population-level control of HIV-1 faces recognized challenges, including the evolution of viral resistance and adherence issues in resource-limited settings. It has long been proposed that viral deletion mutants that conditionally self-renew at the expense of the wild-type virus (i.e., Defective Interfering Particles, DIPs1) could constitute a long-term intervention that circumvents adherence challenges and has a high genetic barrier to resistance, echoing recent approaches2. Theories predict3… 
Conditionally Replicating Vectors Mobilize Chimeric Antigen Receptors against HIV
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References

SHOWING 1-10 OF 72 REFERENCES
Conflicting Selection Pressures Will Constrain Viral Escape from Interfering Particles: Principles for Designing Resistance-Proof Antivirals
TLDR
A multi-scale model to test whether TIPs will maintain indefinite control of HIV at the population-scale, as HIV (‘unilaterally’) evolves toward TIP resistance by limiting the production of viral proteins available for Tips to parasitize finds that TIP-susceptible HIV strains continually outcompete Tip-resistant HIV mutants at both patient and population scales.
Design Requirements for Interfering Particles To Maintain Coadaptive Stability with HIV-1
TLDR
Which molecular characteristics a DIP or DIP-based therapy would need to maintain coadaptive stability with HIV-1 and how therapeutic approaches based on engineered DIPs could be evolutionarily robust and avoid recombination are suggested.
High-throughput generation of transmissible antivirals
TLDR
A new tool to overcome this barrier is introduced: a high-throughput method to generate diverse libraries of barcoded viral deletion mutants at modest expense in a period of fewer than 5 days, and suggests a model of interference where transcriptional asymmetry allows this subset of deletion mutants to compete effectively for a common pool of capsid proteins provided by the wildtype virus.
Theoretical Design of a Gene Therapy To Prevent AIDS but Not Human Immunodeficiency Virus Type 1 Infection
TLDR
Analysis demonstrates that crHIV-1 gene therapy can indefinitely reduce HIV-1 set point to levels comparable to those achieved with highly active antiretroviral therapy, provided crHiv-1 production is more efficient than HIV- 1.
Autonomous Targeting of Infectious Superspreaders Using Engineered Transmissible Therapies
TLDR
The results show that a TIP, engineered with properties based on a recent HIV gene-therapy trial, could stably lower HIV/AIDS prevalence by ∼30-fold within 50 years and could complement current therapies, compared with optimistic antiretroviral therapy or vaccination campaigns alone.
Dynamics of HIV-1 recombination in its natural target cells
TLDR
Increases in viral load may confer a compounding risk of virus escape by means of recombinational diversification, and a method for measuring HIV-1 recombination directly is developed that employs reporter viruses bearing functional enhanced yellow fluorescent protein and enhanced cyan fluorescent protein genes in which recombination produces a modified GFP gene and GFP fluorescence in the infected cells.
Defective lentiviral vectors are efficiently trafficked by HIV-1 and inhibit its replication.
TLDR
HIV-1-based lentiviral vectors that are efficiently packaged and trafficked by HIV-1 are described, allowing a small number of cells initially transduced to spread the vector within a nontransduced cell population.
Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV.
TLDR
It is concluded that gene-modified T cells have the potential to decrease the fitness of HIV-1 and conditionally replicative lentiviral vectors have a promising safety profile in T cells.
HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy
TLDR
Results lead to a simple steady-state model in which infection, cell death, and cell replacement are in balance, and imply that the unique feature of HIV is the extraordinarily large number of replication cycles that occur during infection of a single individual.
Dominant drug targets suppress the emergence of antiviral resistance
TLDR
It is shown that, for an inhibitor of the function of oligomeric capsid proteins of poliovirus, the expression of drug-susceptible genomes causes chimeric oligomers to form, thus rendering the drug-edible genomes dominant.
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