Date Published: December 30, 2009
Publisher: Public Library of Science
Author(s): Maria R. D’Orsogna, Tom Chou, Laurent Rénia. http://doi.org/10.1371/journal.pone.0008165
Abstract: For many viruses, the ability to infect eukaryotic cells depends on their transport through the cytoplasm and across the nuclear membrane of the host cell. During this journey, viral contents are biochemically processed into complexes capable of both nuclear penetration and genomic integration. We develop a stochastic model of viral entry that incorporates all relevant aspects of transport, including convection along microtubules, biochemical conversion, degradation, and nuclear entry. Analysis of the nuclear infection probabilities in terms of the transport velocity, degradation, and biochemical conversion rates shows how certain values of key parameters can maximize the nuclear entry probability of the viral material. The existence of such “optimal” infection scenarios depends on the details of the biochemical conversion process and implies potentially counterintuitive effects in viral infection, suggesting new avenues for antiviral treatment. Such optimal parameter values provide a plausible transport-based explanation of the action of restriction factors and of experimentally observed optimal capsid stability. Finally, we propose a new interpretation of how genetic mutations unrelated to the mechanism of drug action may nonetheless confer novel types of overall drug resistance.
Partial Text: In order to reproduce, viruses must exploit the internal machinery of host cells to synthesize key proteins and assemble new virions. The genetic material of membrane-enveloped viruses is contained within an internal protein capsid enclosed by a lipid membrane. Upon contact with a cell, complex interactions between cellular surface receptors and viral spike proteins ,  induce fusion between viral and host cell membranes, allowing the protein capsid to enter the cell cytoplasm. For many viral species, the genome must also penetrate the nucleus and integrate with the host DNA. Some viruses wait for dissolution of the cell nuclear membrane during mitosis for genomic integration; others take a more active approach by directly transferring their RNA or DNA through nuclear pores. This infection mechanism allows viral reproduction at any stage of the cell cycle, and is utilized by lentiviruses such as HIV –.
Here, we develop a stochastic model describing the transport, transformation, and degradation of viral material in the host cell cytoplasm. Once inside the cell, the capsid of a newly fused enveloped virus encounters a dense actin-rich cortical region that hinders its diffusion . Transport to the nucleus is mediated by microtubules that penetrate this actin-rich layer, creating a highway through the cytoplasm. We thus consider an effective one-dimensional viral motion along microtubule tracks that extend from the cell periphery at to the perinuclear (PN) region near , as shown in Fig. 1. The capsid is assumed to bind to microtubule-associated motors (such as dynein) at before it is convected towards the microtubule organizing center, near the perinuclear (PN) region. Processed viral material is then deposited in the thin PN layer before being transported across nuclear pores .
Eqs. 5 and 4 show that always decreases with increasing degradation rate . The entry probability also increases with and decreases with . However, for various fixed decay rate patterns , can depend on the transformation rates in unexpected ways. Therefore, we first explore in detail how depends on the transformation rates .