Physics of Assembly and Disassembly of HIV

University Of California-Los Angeles, Los Angeles CA

Investigators

Abstract

NONTECHNICAL SUMMARY This award supports theoretical and computational research, and education that builds on the successes in advancing understanding of how small plant viruses and bacteriophage viruses which infect and replicate through a bacterium assemble. These successes were made through the application of methods from the elastic theory of materials and statistical physics. This award supports efforts to develop a physical model for the organization and structural development of the human immunodeficiency virus (HIV), which presents a greater challenge. During an early "immature" stage of its development, HIV has a thick and seemingly robust protein shell composed of the very large proteins that enclose the genome molecule. This shell contains large holes, which is puzzling for a robust container. The shell breaks up through multiple chemical reactions. The PIs plan to develop a numerical model for the formation and break-up of the shell that properly incorporates a theoretical description of elastic materials and concepts from statistical physics to account both for hole formation and the cooperative break-up of the shell. The model will be developed in collaboration with an experimental group that makes synthetic HIV shells. During a second stage, HIV genome molecules are enclosed in a very fragile and thin protein shell. The physical role of this second shell is not understood. The PIs aim to develop a new model for this thin shell, where it plays the role of a chemical reaction vessel during the key HIV process that translates viral RNA into viral DNA. The reactor vessel breaks up when a sufficient amount of stiff DNA material has been produced so as to exert sufficient force on the container wall. The PIs will model the fracture of this mature shell using the theory of the elasticity of materials. The last part of the project involves developing a numerical model for the very early development of the HIV shell inside the host cell, which will also be carried out in collaboration with experimentalists. This research involves the application of methods and ideas from materials research to advance understanding of how large viruses self-assemble. Apart from potentially leading to new strategies for managing viral diseases, the research brings insight more generally to the process by which large molecules and other structures made from atoms self-assemble from their constituent atomic and molecular building blocks. The fundamental principles may lead to new ways to design new materials and manufacture them from atomic and molecular building blocks. TECHNICAL SUMMARY This award supports theoretical and computational research, and education that builds on the successes in advancing understanding of the assembly of small plant and bacteriophage viruses through the application methods from elasticity theory and statistical physics. The much larger human immunodeficiency virus, HIV-1, operates on very different principles and understanding of them is limited. This award supports efforts to resolve three puzzles: (1) Retroviruses like HIV undergo a massive structural maturation transformation as part of their life cycle in which a second "mature" viral particle is assembled in the interior of the first "immature" particle. After infection, this mature particle is inserted into the cytoplasm of the host to deliver the viral genome. This transformation is coordinated by the huge Gag polyprotein. The immature form of the HIV virus includes a structurally disorganized shell of Gag proteins that contains large, irregularly shaped holes. Why these holes do not close up is a puzzle. (2) The thermodynamic affinity of viral RNA molecules for Gag is about the same as that of competing non-viral RNA molecules, which are much more abundant in the host cell during the initial assembly; but somehow Gag quite efficiently selects the viral RNA molecules for encapsidation. Can a delicate interplay among generic electrostatic and specific non-electrostatic interactions as well as a structural transformation of Gag explain this puzzle? (3) The conical mature capsid of HIV is more fragile than the capsid of just about any other virus, yet mutations that strengthen the shell or that change its shape have a strongly negative impact on HIV infectivity. These three puzzles will be addressed through the application of concepts and methods borrowed from different areas of soft-matter physics, biological physics, and statistical mechanics. All three projects will be carried out in close collaboration with labs that focus on the biophysical properties of HIV. A physical understanding how it is possible for Gag to select molecules from a pool of similar molecules without either having an enhanced thermodynamic affinity and without any proofreading would be of fundamental interest. Next, the many-body physics of particles confined to a spherical surface is believed to have a minimum energy state characterized by scar-like defects. Assemblies of Gag particles on spherical templates exhibit just such scars. These scars appear to evolve into the irregular holes mentioned above when the template is removed. Connecting the fundamental physics of particles confined to deformable spherical surfaces with the immature HIV capsid would provide a stimulus for the further development of this field. Finally, though the physics of resilient viral capsids has been investigated extensively, the physics of fracture of very fragile protein shells is not understood. Yet controlled fracture of capsids - as practiced by HIV - may be a key step for the design of new drug delivery systems.