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Except by Stealth

February 14, 2011

Orf63 is a viral homolog and inhibitor of NLRP1William Hazlitt, the great English, 19th century essayist, could wax long and philosophically about the big stuff.  Life.  Death.  How to use a semicolon. He almost certainly knew little, if anything, about virology.  But Hazlitt has left behind a 12-word commentary on the human pursuit of perfection that captures the evolutionary plight of viruses.  He wrote, “No one ever approaches perfection except by stealth, and unknown to themselves.” 

If Hazlitt could have slipped into a white lab coat and added a Ph.D. after his surname, he would have explained it’s a matter of natural selection.  Viruses, unknown to themselves, have adapted to life’s jungle out there, emerging as evolutionarily well honed to pursue their life cycle by stealth. 

A classic example is Kaposi’s sarcoma-associated herpesviruses, or KSHV, also called human herpesvirus 8. KSHV is a double-stranded DNA tumor virus that has an affinity for infecting different types of cells, including endothelial cells and lymphocytes.  Once inside a cell, KSHV tethers its DNA to a chromosome and either lies low or turns lytic. In the latter case, the virus kills the cell, while replicating and dispersing copies of its DNA for further infection.  The virus is associated with causing several human cancers, including Kaposi’s sarcoma, a common complication of AIDS. 

What’s fascinating about KSHV is just how multi-faceted its capacity for stealth is.  A quarter of its proteins have been shown to regulate some aspect of the human immune system.  Many are encoded in genes that the virus has snatched to varying degrees from its host. 

In the January 21 issue of the journal Science, NIDCR grantees and colleagues add another stealth weapon.  This one is mediated by the previously uncharacterized Orf63 tegument protein.  The tegument is a region of the virus, between the capsid and envelope, where surface proteins cluster. The researchers discovered that Orf63 is the viral homolog of human NLRP1. However, Orf63 lacks NLRP1’s activation domains, suggesting the viral protein binds and inhibits its human counterpart. 

Why target NLRP1 and block its activation?  To impair innate immunity, our immune surveillance system that non-specifically patrols for telltale chemical signs of invading pathogens, such as KSHV.  NLRP1 belongs to the larger NLR family of pathogen-recognition receptors.  When activated, NLRs trigger the formation of large, multi-protein complexes called an inflammasome.  The complex, in turn, sets in motion the processing of the key immune signaling proteins, IL-1β and IL-18, to blow the whistle on pathogens, such as KSHV.  The authors also noted that KSHV needed to block NLRP1 to efficiently generate new virus, suggesting that modulation of NLR-mediated innate immunity is important for the lifelong persistence of herpesviruses. 

  • Gregory SM, Davis BK, West JA, Taxman DJ, Matsuzawa S, Reed JC, Ting JP, Damania B. Discovery of a viral NLR homolog that inhibits the inflammasome, Science. 2011 Jan 21:331(6015):330-4. 


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This page last updated: February 26, 2014