Читать книгу Principles of Virology - Jane Flint, S. Jane Flint - Страница 256

As the Trojans brought the vehicle of their destruction into their city, so do cellular processes bring viral particles inside the cell. Although the initial encounter between a single virus particle and a cell is random, viral proteins often exploit specific cell surface molecules to secure specific docking to their target cells. A diverse set of cell surface molecules are found to serve as viral receptors. On the other hand, the same molecule or molecules belonging to the same family of proteins can serve as receptors for divergent viruses.

Receptor binding is but the first step, and often initiates major conformational changes in the virus particles. For enveloped viruses, such conformational changes in the envelope glycoprotein eventually drive the fusion of viral and cellular membranes. For nonenveloped viruses, conformational changes generally lead to disruption of the cellular membrane and the delivery of a subviral complex to the cell interior. In both cases, these changes ultimately allow the viral genome to access a cellular compartment that enables replication. Although the mechanisms of entry for the various virus families appear vastly different, certain themes repeatedly emerge. Structural rearrangements in viral proteins that enable entry are often dependent on proteolytic cleavage events that occur either during assembly in the virus-producing cell or at the surface or within endosomal compartments during entry into the target cell. The acid pH found in endosomes is a common trigger for conformational rearrangements that enable entry. Such conformational changes almost always result in the exposure of hydrophobic protein sequences that can interact with and disrupt cellular membranes and allow access to the cell interior.

The cell is often not an idle target but an active participant in viral entry. Engagement of cell surface receptors by virus particles can trigger signal transduction pathways that lead to cytoskeletal rearrangement and endocytosis. Virus particle transport within the cell can be within vesicles, whose transport mechanisms are quite well understood. Conversely, vesicle-independent transport of viral or subviral particles on the cytoskeletal network is less well characterized. Notably, entry of various components of virus particles, nucleic acids and proteins, into the interior of the cell can be detected by specialized sensors that alert the innate immune system and elicit antiviral responses (a topic covered in Volume II, Chapter 3).

For some viruses, the final destination, and the site of genome replication, is the cell’s nucleus. The nuclear envelope raises an additional barrier to virus entry, with a plethora of proteins regulating access to the nuclear interior through the nuclear pores. Virus particles or subviral structures are too large to pass through the nuclear pore. Therefore, interactions with the specialized nuclear transport machinery are usually necessary for subviral structures to be escorted into the nuclear interior. This process is not well understood for many viruses.

Many questions about specific steps in the entry pathways of many viruses remain, including the elucidation of entry pathways used in whole organisms, a technically challenging endeavor. Understanding how entry proceeds and how particles “disassemble” to release the viral genome at the site of replication will allow us not only to develop specific interventions for prevention of virus infections but also to manipulate virus particles for use as viral vectors.