When a teen-ager or young adult comes down suddenly with a sorethroat, high fever, extreme fatigue and swollen armpits, a wise parentor physician may suspect mononucleosis, or "kissing disease" _ themildest of all sexually transmitted infections.
In mouth-to-mouth contact, a carrier of Epstein-Barr virus (EBV)conveys its virions to the party of the second part, who may not haveimmunity to EBV. Most children in the world acquire antibodies tothe virus very early in life, because in areas of minimal to moderatesanitation, saliva touches other things than lips on its way tospreading EBV.
Ironically, automatic dishwashers and other agents of our cleaner-than-clean lifestyle have spared current generations of middle-andupper-class youth in First-World countries from childhoodimmunization against EBV. This hygienic environment leaves themwide open to mono when coming of age.
EBV's virions lie latent for life, but only in salivary glands and in Blymphocytes of the humoral immune system. More serious than thekissing disease, which goes away in a week or two, are the cancersthat the universal virus causes:
* Burkitt's lymphoma, a malignancy of the lymph glands,afflicts children in East and West Africa.
* Nasopharyngeal carcinoma, a fatal tumor of the nasalpassages and throat, is endemic in Southeast Asia, particularly SouthChina.
* Hodgkin's disease: 40 percent of cases involve EBVinfection
* Lymphoblastic lymphomas threaten some organ-transplantrecipients, and people with immune deficiencies, such as AIDS.
In every one of these malignant tumors, EBV ostentatiously leaves itsfingerprint -_ a viral phosphoprotein called EBV-encoded NuclearAntigen (EBNA1).
Like HIV, EBV is a wily dodger among viruses. HIV particles arestudded with conspicuous antigens, which have sparked and fueled anentire biotech industry, trying to create an AIDS vaccine.
EBNA1 evades the immune system by means unknown, andapparently unknowable. That ubiquitous EBV antigen, like a clevercriminal, is invisible to the immune system. Jack the Ripper comes tomind, who evaded battalions of Scotland Yard sleuths. The policenever found an accomplice willing to turn state's evidence and pointJack out to them for capture.
Low-Profile Viral Perpetrator Keeps Out Of Sight
In the human immune system, the "wise-guy" that fingers apathogenic antigen is called a Class I histocompatibility molecule. Itsjob is to process the alien antigen and "present" it to the cytotoxic Tlymphocyte enforcers. These white blood cells then act as judge, juryand executioner, killing the invader on sight.
But they can't sight that EB nuclear antigen-1, and there's the rub.
Seeking in the dark for its viral cloak of invisibility, a team of tumorimmunologists at Sweden's Karolinska Institute have found a clue inthe protein products of EBNA1's junk DNA.
Their preliminary finding appears in today's issue of Nature, datedJune 22, and titled, "Inhibition of antigen processing by the internal-repeat region of the Epstein-Barr virus nuclear antigen-1." Thepaper's principal author is virological immunologist Maria Masucci,who runs Karolinska's EBV immune-response laboratory.
"In Burkitt's lymphoma," she told BioWorld Today, the antigen weare discussing in this Nature paper, EBNA1, is the only antigenexpressed. Failure to present it may play a role in the lack ofimmunogenicity and evasion of this disease.
"The problem we had to face in approaching this question," she wenton, "is that we will not have cytotoxic T-cell responses to thisparticular virus, or to this particular antigen."
To tackle that catch-22, Masucci and her co-authors took a knownand visible target epitope from a different EBV antigen, EBNA4.Using recombinant vaccinia viruses expressing chimeric proteins,they inserted this distinguishing EBNA4 immune marker into theEBNA1 protein, which contains a repeat region of two amino acids,glycine and alanine (Gly-Ala). At the same time, they latched thesame epitope onto a deletion mutant of EBNA1, from which they hadremoved the Gly-Ala repetitive stretches. Then they expressed theseconstructs in human fibroblasts.
The repeat-lacking protein turned out to be quite readily "seen" bythe antigen-presenting molecules and cytotoxic lymphocytes of anormal immune system. The repeat-harboring version, even thoughflagged with the known-visibility epitope, wrapped itself in that cloakof immune invisibility.
Potential Use Seen In Gene-Therapy Vectors
To double-check their finding that Gly-Ala was the cloak, Masucci'steam transferred the region of the EBNA1 protein that included theGly-Ala repeats into the EBNA4 protein, "and asked whether thenthe epitopes of EBNA4 would be presented from this chimericprotein," Masucci said, "They were not," she answered, "whichsuggests that the Gly-Ala repeat itself can somehow deliver a signalthat prevents processing of a protein for presentation to the cytotoxiclymphocytes."
The Karolinska, she observed, "is trying to file a patent for thisparticular finding. It could potentially be used to prevent processingor presentation of other antigenic proteins. This may be of interestwhere one would want to inhibit immunogenicity.
"For example," she observed, "there are proteins that are antigenic intransfer vectors, which are used for gene therapy."
In her paper, she concluded: "[Our finding] supports the view thatpresence of the Gly-Ala repeats may be directly involved in thefailure of the E1/N4 chimera to sensitize target cells to lysis . . . It is .. . not surprising that viruses have evolved sophisticated mechanismsto escape cytotoxic lymphocyte recognition." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.