Virology, uncoating

In virology, uncoating refers to a complex process that leads to the release of genomic nucleic acid from the capsid and viral envelope. This tightly regulated, multi-step molecular process occurs within the cytoplasm of infected cells before the viral genome enters the nucleus (Kilcher S et al. 2015). Viral penetration into the host cell and uncoating often merge seamlessly. However, after the uncoating process, the viral genome is not naked but usually associated with proteins in the cytoplasm or nucleus.

Most virus capsids are assembled during their morphogenesis from regular capsomer units, resulting in spiral or icosahedral structures. Regardless of their architecture, all viral capsids have a built-in capacity for "disassembly", i.e., disassembly of the capsid structure, also referred to as structural metastability (Helenius A 2018). Conceptually, virion morphogenesis and uncoating are inverse reactions. The ability of viruses to perform such opposite reactions is also referred to as the "assembly-uncoating paradox".

Viral genomes are condensed and packaged into stable proteinaceous capsids that protect them during transport from one cell or host organism to another. During virus entry (penetration), capsid shells are disassembled in the complex, tightly regulated, multi-step uncoating process.

Depending on the virus, uncoating takes place

• a) directly at the cell surface of the host cell by fusion of plasma and viral envelope (for paramyxoviruses, retroviruses)
• b) after uptake of the virus particles into endosomes by fusion of the endosomal membrane of the host cell and the viral envelope at acidic pH (for influenza viruses)
• c) in the case of non-enveloped viruses, after endocytosis in the endosomes and on the nuclear membrane of the host cell (e.g. in the case of adenoviruses) or in lysosomes (in the case of reoviruses).

DNA-containing viruses, on the other hand, must bring their genome unharmed through the cytoplasm to at least the nuclear membrane. There, they release their DNA through the pores of the membrane into the nucleus. The empty protein envelope disintegrates (Hof H et al. 2019) .

Since genome release is a critical step in the life cycle of any virus and a prerequisite for genome replication, understanding the molecular details of viral capsid disassembly and genome delivery programs may reveal new drug targets and therapeutic opportunities. For example, M2 inhibitors (e.g., amantadine or rimantadine) block membrane protein M2, which is necessary for influenza A virus uncoating.

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