Intelligence agencies the world over spend much of their time andresources trying to ferret out enemy moles operating under coverwithin their own organizations.
Now it turns out that the AIDS virus, in its covert action ofpenetrating and infecting human cells, employs mole-like moleculesinside those target cells.
Without these newly discovered confederate receptors lurking on thesurface of immune-system T lymphocytes and macrophages, an HIV-1 virion can't get beyond that surface. With those co-conspiratorsunlatching the front door from inside, as it were, they can fuseunimpeded with the now defenseless cell membrane, then enter, andmove into infection mode.
The May 10, 1996, Science tells the story: "HIV-1 entry cofactor:Functional cDNA cloning of a seven-transmembrane G protein-coupled receptor."
The paper's principal author, molecular virologist Edward Berger,has christened this traitorously permissive receptor "fusin," because itpermits the viral envelope to fuse with the cell membrane. Bergerheads the molecular structure section at the National Institute ofAllergy and Infectious Diseases (NIAID), in Bethesda, Md.
Since the mid-1980s, AIDS researchers have equated entry of HIV-1with another receptor, CD4, which studs the surface of T cells andmacrophages _ marked by the virus for infection and destruction. Itattacks CD4+ T cells in the symptomatic stage of AIDS;macrophages before the disease breaks out of its latent phase.
Berger and his co-authors uncovered evidence that some HIV-1-positive patients escape the overt disease for years, precisely becausethey lack cell-surface fusin. Their discovery also explains why mostsubhuman forms of life _ even animals modified to express CD4 _brush off HIV infection; their cells don't make fusin. It seems that thegene, or genes that encode fusin are specific to the human species.
What that protein does for normal, healthy humans is still a black-boxquestion.
When the NIAID team analyzed fusin's DNA sequence, Berger toldBioWorld Today, they found it resembled that of a "giantsuperfamily" called G protein-coupled receptors, "the biggestsuperfamily in the genome, with several hundred genes all over thechromosomes," which perform various tasks all over the body."Interestingly," Berger said, "other members of this family areexploited for entry into human cells by different pathogens, includingthe malaria parasite Plasmodium vivax."
"Most of these receptors," he added, "are complexed with specializedproteins, called G proteins, that send signals to the interior of the cell,and are the specific targets of many drugs currently in use for avariety of ailments."
When Berger's team took permissive (i.e., HIV-1-susceptible) CD4+cells from healthy human volunteers, they were able to block thefusin receptor by monoclonal antibodies to it. This further confirmedthe receptor's auxiliary role in viral fusion and penetration.
"We're predicting," Berger said, "that in addition to the molecule weisolated, which we call fusin, there must be other cofactors for strainsof HIV-1, which we're now trying to isolate. Not all strains of HIV-1use fusin," he pointed out. The strains that appear late in the diseaseprocess, when the patient is going from asymptomatic tosymptomatic, are the strains that use fusin. Whereas the strains thatare present in the asymptomatic phase probably use another moleculethat we haven't identified yet.
Berger cites from his work "three take-home messages for the biotechand pharmaceutical industries:
* "One, for drug development, is that there's a potential new target.We've developed a very good assay for screening drugs that blockfusion, mediated by fusin.
* Another is making a transgenic animal model that expresses fusinplus CD4 for drug and vaccine trials." His laboratory has alreadyconstructed rabbits that express human CD4, and are now working toincorporate fusin genes as well.
* "Finally," Berger observed, "is the vast unknown, which is thewhole window of opportunity that's been opened by this discovery _to try to understand AIDS pathogenesis. That's a little bit further intothe future." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.