Viral entry mechanisms: simplicity drives complexity

MINIREVIEW SERIES

Viral entry mechanisms: simplicity drives complexity Deepak Shukla Departments of Ophthalmology & Visual Sciences and Microbiology & Immunology, University of Illinois at Chicago, IL, USA

Most viral genomes (DNA or RNA) express a relatively small number of genes, and the viral capsids contain one (or few) kind(s) of protein and may or may not require an outer lipid membrane (envelope) for their existence; nevertheless, viruses succeed in invading and hijacking much more complicated host cells to promote their life cycles. As obligatory intracellular parasites, the first step in a viral lifecycle is normally attachment to a host cell membrane receptor. The attachment then initiates a complex series of events that results in the release of the viral genome into the host cell. Crossing the plasma membrane barrier is not a simple task, which may be why viral entry proteins demonstrate complex and multi-functional natures. Often, multiple viral proteins work in concert with many cellular partners to ensure entry. Even then, finding the right location, both on the right cell and at the right time, is crucial. To enhance their entry prospects, viruses rely on versatile ways to enter cells and exploit multiple cellular organelles to facilitate efficient entry. In order to develop an appreciation of the commonality and diversity of entry pathways, the current minireview series focuses on three diverse families of pathogenic human viruses. The minireview by Sapp and Bienkowska-Haba covers our latest understanding of papillomavirus entry. Papillomaviruses are highly prevalent epitheliotropic viruses that are capable of causing many forms of cancer and other symptomatic human diseases. The viral family represents over 100 non-enveloped members characterized by short DNA genomes encoding approximately eight different proteins. Entry begins when the cell surface heparan sulfate is exploited for attachment. A complex series of events then facilitates viral capsid penetration into the host cytoplasm and

subsequent trafficking of the incoming viral genomes to the nucleus. The emerging data paint a complex picture by which a small number of viral proteins gain control of intracellular transport for viral trafficking. The complexity associated with viral entry and membrane fusion proteins has been examined well by ongoing research on paramyxioviruses. The minireview by Clinton-Smith and colleagues describes the intricate nature of viral proteins and how changes in protein conformation regulate the entry of enveloped, negative-strand RNA viruses. Paramyxioviruses express genes encoding only six to eight proteins and devote at least two glycoproteins to entry. The minireview also describes some unique entry pathways that the viruses can use and how new zoonotic members may adapt to human infections. The third minireview by Akhtar and Shukla focuses on herpes simplex virus (HSV) entry. This is a much larger DNA virus encoding 70 or more proteins. The mechanism that HSV uses for entry is one of the most complicated procedures studied thus far, utilizing at least five glycoproteins during entry alone. This complexity continues to increase as new pathways and participants are identified. It appears that viral proteins not only partner with cellular proteins, but also interact in an orderly manner with each other to promote entry in cell-type specific ways. New reports indicate that HSV and other viruses can use novel extracellular transport pathways for targeted landing on the cell bodies. The three minireviews also highlight the fact that, despite their apparent diversity, viruses may have much in common too. Identifying such commonality at the very first step of pathogenesis (i.e. entry) may be of value in safeguarding the human population from viruses in general.

Deepak Shukla is an Associate Professor in the Departments of Ophthalmology & Visual Sciences and Microbiology & Immunology at the University of Illinois at Chicago (UIC). He received his PhD in Microbiology from UIC with Philip Matsumura and postdoctoral training with Patricia Spear at Northwestern University, with whom he discovered 3-O sulfated heparan sulfate as an entry receptor for HSV-1. For his contributions to herpesvirus research, he was awarded the 2001 American Herpes Foundation research award for excellence and the Lew Wasserman Merit Award from Research to Prevent Blindness USA in 2009. His current research focuses on HSV entry mechanisms. doi:10.1111/j.1742-4658.2009.07399.x

FEBS Journal 276 (2009) 7205 ª 2009 The Author Journal compilation ª 2009 FEBS

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