By David N. Leff
Right now, there are almost as many human herpesviruses (HHV) as there are players on a baseball team. And like that line-up, each of the eight HHVs wears its own number and plays a designated position.
Here is the HHV program card:
* Almost everyone is familiar with HHV-1, Herpes labialis, which causes cold sores -- fever blisters.
* HHV-2, Herpes genitalis, is mercifully less common; it inflicts genital lesions, and perhaps cervical cancer.
* HHV-3, Herpes varicella, causes chickenpox in children and herpes zoster (shingles) in grown-ups.
* HHV-4 is better known as Epstein-Barr virus, perpetrator of a fatal African cancer, Burkitt's lymphoma. It's the only HHV to date convicted of causing malignancy.
* HHV-5, Cytomegalovirus, is infectious in people and pigs, among other targets.
* HHV-6, Roseolovirus (a.k.a. pseudorubella), is a severe infection of infants and small children.
* HHV-7, recently added to the roster, has, as yet, no common name or defined pathology.
* HHV-8, newest recruit to the human herpesvirus line-up, is already implicated in Kaposi's sarcoma, and circumstantially in the pathogenesis of HIV itself. (See BioWorld Today, Aug. 29, 1996, and May 4, 1995, both p. 1). It's the commonest cancer to afflict AIDS patients, at an incidence of 50 percent.
HHV-8 is now designated Kaposi's sarcoma-associated herpesvirus (KSHV). This makes it the second HHV, after Burkitt's lymphoma, to be charged with causing cancer.
The latest evidence in HHV-8's indictment appears in the current issue of Nature, dated Jan. 23. Its title: "Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation."
One seemingly smoking gun linking HHV-8 to malignancy is its genomic homology to HHV-3, the Epstein-Barr virus of Burkitt's lymphoma, and the lymphocyte-transforming Herpes Saimiri monkey virus.
Marvin Gershengorn, a senior author of the Nature article, told BioWorld Today: "KSHV has been found in most, if not all, the tumor tissues of Kaposi's sarcoma [KS] patients, and in cell extracts of patients with a certain rare type of B-cell lymphoma."
But he also made the point: "In my reading, it is not clear as to whether the spindle cells seen in the Kaposi tumor, and which HIV can affect, are truly cancerous, or just hyperproliferating."
Gershengorn, who directs the division of molecular medicine at Cornell University Medical College, in New York, then pointed out: "The issue comes down to whether the virus is there, and really participating in pathogenesis of KS, or not. Is it really playing an important pathogenic role, or is it simply a passenger virus?"
Describing the crucial role of G-protein-coupled receptors (GPCR) in the search for therapeutics against KS, he pointed out that GPCRs "in the human genome represent 1 to 2 percent of all the proteins made in our bodies." Moreover, "50 to 60 percent of the drugs now used clinically -- such as anti-histaminics, the beta blockers, etc. -- are directed at GPCRs.
"G protein receptors," Gershengorn explained, "don't know how to generate a signal, but they do activate G proteins ['G' for guanine-nucleotide binding]. These interact with an effector molecule, an enzyme or an ion channel, for example, which then generates the intracellular message."
He and his co-authors reported discovering a G-protein chemokine receptor that behaved abnormally.
"Most receptors," he said, "remain in 'off' mode until turned on by a hormone, a growth factor or a neurotransmitter. The GPCR we found is always 'on,' even though there was no chemokine ligand or agonist protein around that should normally turn them on."
An Exciting Find
He called this maverick receptor "remarkable; something that could not be predicted by simply looking at its amino-acid sequence."
The "exciting finding" that followed, Gershengorn continued, "was that when we expressed those abnormal receptors in fibroblast cell lines, that led to stimulation of fibroblast cell proliferation. From that we would hypothesize that if this was sufficient or necessary for tumorigenesis, if one could develop agents that would turn this receptor off, we would have a very important drug to either prevent or treat these KS tumors."
Classical drugs, he noted, act as antagonists that work only to inhibit an agonist from acting.
"What we and other laboratories are studying now," he said, "are a subset of antagonists that do something all by themselves. They can interact with a receptor, and if the receptor was constantly 'on,' the compound could turn it off."
In the Nature paper, Gershengorn observed, "we reported finding a number of cytokine analogs that will interact with the receptor, but none of them, unfortunately, turn it off. So that's what we're hunting for."
One hunting ground, he suggested, would be "looking in the vaults of pharmaceutical companies for other compounds that may turn the receptor off. That might prove to be a fruitful task."
In an editorial accompanying the article, immunologist Philip Murphy, of the National Institute of Allergy and Infectious Diseases, commented: "If they [Gershengorn and colleagues] are right, KSHV G-protein-coupling receptors could be an important target for the development of new AIDS therapies." *