The Physical Virology Group

Carnegie Mellon University, Department of Physics
Principle Investigator: Prof. Alex Evilevitch

http://www.cmu.edu/physics/index.html
 

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Research Outline

The majority of viruses possess spherical, icosahedral protein shells with radii varying between 10 nm and 100 nm and with thicknesses of a few nanometers corresponding to single protein layer. Viral capsids protect genomes that are tens of microns in contour length. Sufficient genome encapsidation implies that the virus must be stable enough to withstand internal forces exerted by its packaged genome and external forces from its environment. Yet, it must be unstable enough to rapidly release its genome in the cell during infection. Thus, there must exist a unique match between the virus’s genome length and capsid size and strength that is adjusted to the biological and physical properties of the host cell. Internal genome pressure, reaching tens of atmospheres as a result of strong confinement, is required for phages and many other dsDNA viruses to be able to infect by passive ejection of its genome. Besides from determining this pressure, we also found that it provides additional support to the strength of the viral capsid helping the virus survive external deformations imposed on it between infections.

Our group uses biophysical approaches in order to learn about the fundamental physical principles that control viral genome encapsidation and release as well as capsid stability. This research program takes advantage of the high-resolution cryo electron microscopy, AFM, light scattering and microcalorimetry. Furthermore, our findings provide tools for the rational design of therapeutic agents that selectively interfere with the encapsidation process, and in addition tools to improve encapsidation in vitro in order to make stable vectors for gene delivery.

How to interfere with success of the virus?
Success of the virus, i.e. the infectivity, depends on the match between genome length and capsid size:
1. Ability to bring viral genome in the cell

VIRAL GENOME: EJECTION AND PACKAGING
  • Pressure inside Human Herpes Simplex Virus (HSV).
  • Control of capsid pressure by varying electrolyte concentrations. (Ref. 16, 10, 9)
  • Ion distribution in viruses studied with EFTEM.
  • Direct calorimetric measurements of energy stored in the packaged DNA of viral particles. (Ref. 21)
  • DNA structure inside the viral capsids.
  • Dynamics of viral DNA ejection. (Ref. 13, 11)
  • Microfluidics as a tool to study viral infection in vivo.
  • Osmotic pressure - promoting and resisting viral DNA release (Ref. 17, 16, 14, 10, 9, 8, 7, 6, 5)

2. How to survive external mechanical capsid stress

before DNA release?


VIRAL CAPSID: MECHANICAL PROPERTIES, PACKAGING MOTOR, AND SELF-ASSEMBLY

  • Effect of internal DNA pressure on viral capsid stability. (Ref. 12)
  • Evolutionary optimization of viruses.
  • Viral DNA packaging motor – strongest molecular motor known.