Multiple-hit inhibition of infection by defective interfering particles

Kristen A Stauffer Thompson1, Grzegorz A Rempala2, John Yin1

  • 1Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706-1607, USA.

Insights

Defective interfering particles (DIPs) impact virus growth differently based on their dose. Low doses amplify both virus and DIPs, while medium and high doses inhibit their replication.

Area of Science:

  • Virology
  • Molecular Biology
  • Systems Biology

Background:

  • Defective interfering particles (DIPs) are virus-derived entities that require helper virus for replication.
  • While DIPs are known to inhibit viral growth, their own replication dynamics and dose-dependent effects are poorly understood.

Purpose of the Study:

  • To investigate the quantitative impact of defective interfering particle (DIP) dose on both DIP and helper virus production during co-infection.
  • To develop and evaluate mathematical models describing the complex interactions between viruses and DIPs.

Main Methods:

  • Co-infection of BHK cells with vesicular stomatitis virus (VSV) and varying doses of VSV DIPs.
  • Yield-reduction assays to quantify virus and DIP production.
  • Mathematical modeling to analyze dose-response data and explore different mechanistic assumptions.

Main Results:

  • Three distinct co-infection regimes were identified based on DIP dose: low DIP (amplification of both), medium DIP (inhibition of both), and high DIP (limited virus recovery, further DIP inhibition).
  • DIPs exhibit a dose-dependent effect, inhibiting or promoting virus and DIP production.
  • Serial passage experiments provided estimates for de novo DIP generation frequency.

Conclusions:

  • DIPs play a complex, dose-dependent role in viral replication dynamics.
  • Mathematical modeling is crucial for understanding the quantitative impact of DIPs on virus growth and infection spread.
  • This study provides a framework for predicting DIP-virus interactions in various infection scenarios.

Related Concept Videos

Inhibitors of Virion Maturation and Assembly01:19

Inhibitors of Virion Maturation and Assembly

As part of their replication cycle, certain viruses synthesize long precursor proteins called polyproteins within infected host cells. In human immunodeficiency virus (HIV), two major polyproteins are produced: Gag and Gag-Pol. The Gag polyprotein supplies the structural components of the virus, while Gag-Pol includes essential viral enzymes such as reverse transcriptase, integrase, and protease. After synthesis, these polyproteins move to the host cell membrane, where they assemble into an...
Inhibitors of Viral Protein Synthesis01:30

Inhibitors of Viral Protein Synthesis

Protein synthesis is indispensable for viral replication, as viruses lack the cellular machinery required for this process and must hijack the host's translational apparatus. In response, host cells deploy a critical innate immune defense involving interferons, specialized cytokines that play a central role in inhibiting viral propagation.Upon viral detection, infected cells release interferons that bind to receptors on adjacent uninfected cells, activating the JAK-STAT signaling pathway and...
Experimental RNAi02:15

Experimental RNAi

RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
Immunodeficiency Diseases01:25

Immunodeficiency Diseases

Immunodeficiency disorders are conditions in which the immune system's ability to fight infectious disease and cancer is compromised or entirely absent. The immune system comprises a complex network of cells, tissues, and organs that work together to protect the body from potentially harmful invaders. When this system is deficient or not functioning properly, it leaves the body susceptible to infections, diseases, or other complications.
There are three main causes of immunodeficiency disorders...
Inhibitors Of Virion Release01:25

Inhibitors Of Virion Release

Viral replication and dissemination rely on efficient mechanisms for host cell entry, genome replication, assembly, and release. Influenza viruses, such as types A and B, are negative-sense single-stranded RNA viruses with a segmented genome, that depend on two critical surface glycoproteins to carry out these processes: hemagglutinin (HA) and neuraminidase (NA). HA initiates infection by binding to sialic acid residues on the surface of host epithelial cells, facilitating receptor-mediated...
RNA Interference01:23

RNA Interference

RNA interference (RNAi) is a process in which a small non-coding RNA molecule blocks the post-transcriptional expression of a gene by binding to its messenger RNA (mRNA) and preventing the protein from being translated.
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...