In some ways, the duel to the death between HIV and the immunesystem is like a chess match between grand masters.
One of those analogies between the board game and the AIDSstruggle we owe to Thomas Henry Huxley, the great biologist whowas Darwin's mentor. "On the chess board," Huxley wrote in 1868,"the player on the other side is hidden from us."
That is literally the nub _ and the rub _ of two adjacent papers intoday's Nature. Both reveal the same gambit that the AIDS virusplays to advance its pieces toward checkmating its opponent, the Tcell.
That viral strategy takes place in four decisive opening moves, ofwhich one remains hidden:
First, HIV's envelope glycoprotein 120 (gp120) binds to its CD4receptor on the T cell surface.
Second, thus engaged, the gp120 contorts itself out of shape and intoa new conformation, which exposes the crucial hidden structure.
Third, that newly revealed gp120 epitope complexes with a secondT-cell receptor, a co-factor chemokine molecule named CCR-5.
Fourth, from its new position, the gp120 reaches down into the viralmembrane to put a new piece, glycoprotein 41, in play. Protected andpropelled by the two committed co-factors, gp41 penetrates the Tcell's defenses, to penetrate the doomed cell.
Biochemist John Moore, an AIDS researcher at The RockefellerUniversity's Aaron Diamond Research Center, in New York,employs a more ballistic metaphor to recount HIV's winning four-move gambit:
"gp120," Moore told BioWorld Today, "triggers the coiled springthat fires gp41 into the host cell membrane. Actually, it looks like atwo-stage trigger. The first pull attaches to CD4. The second, whichfires the gun, complexes with CCR-5. Quite what happens betweenthe trigger being pulled and the gp41 bullet leaving the barrel is alittle bit obscure."
Moore is senior author of one of the papers in today's Nature. Itstitle: "CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5."
Its non-identical twin article is headed: "CD4-induced interaction ofprimary HIV-1 gp120 glycoproteins with the chemokine receptorCCR-5." That one's principal author is molecular virologist JosephSodroski, who chairs the division of human retrovirology at the DanaFarber Cancer Institute of Harvard Medical School, in Boston.
Two Papers, One Finding
"It's been known for at least a few months now that these chemokinereceptors, CCR-5 and fusin (see BioWorld Today, Sept. 27, 1996, p.1) can act as entry co-factors for HIV infection, Sodroski toldBioWorld Today. "What we're really providing in this paper is amechanism whereby they work."
That mechanism, said Moore, "would presumably be similar forfusin, which is the other second receptor that binds different types ofHIV."
Just where that occult binding site is located, "we do not knowprecisely," Moore said. "We know that it's almost certainly acomplex, discontinuous structure that's probably hidden under thevariable loops of gp120. And it's a relatively conserved region,"remaining relatively constant through all of HIV's never-endingmutations.
"Finding exactly where it is," he observed, "depends on the eventualidentification of the gp120 crystal structure of gp120, which nobodyyet has."
Sodroski allowed that "We are now trying to dissect that structure."He pointed out that "exposing that hidden region of gp120 "poses aproblem for the virus. Exposure would raise antibodies against it. Soits strategy includes keeping it concealed until the last moment beforeattachment of the virus to the second receptor, CCR-5. Then it peelsoff its protein layers, and forms its epitopes, but too late for antibodyattack."
HIV-1 comes in two persuasions:
* Primary viruses, which bind to CCR-5 as their second receptor,Moore explained, "are the predominant viruses transmitted duringsexual transmission. They're really the most important AIDS virusesaround."
Fusin By Any Other Name . . .
* T cell-adapted laboratory strains are also found in humans, butemerge late in disease and are not transmitted as often. Their secondreceptor is fusin, now called CXCR-4. (See BioWorld Today, May13, 1996, p. 1.)
Moore and Sodroski are both working on CXCR-4, for whichreagents have just become available. "I'm sure its mechanism will befundamentally the same as CCR-5," Moore observed.
He and his group are currently interested as well in how theneutralizing antibodies work. And the way to start addressing thatquestion is to try to set up a mutually competitive interaction betweengp120 and CCR-5. Moore added that "Joe [Sodroski] had basicallythe same methodology."
As for new therapeutic drugs spinning off from this research, Moorecommented: "Our work _ and Joe's, which is on the same parallel _would help us understand things that often lead to an unanticipatedspin-off in the future. But I would think that the course of work ondeveloping drugs to block CCR-5 would go on anyway, and wouldnot be radically changed by these papers."
Three of the 10 co-authors on the Aaron Diamond paper are fromProgenics Pharmaceuticals Inc., of Tarrytown, N.Y. "They helpedmake cell lines, supplied the gp120 molecules and providedintellectual support, but with no financial arrangements," Moore said.
Dana Farber's Sodroski is a scientific consultant to LeukoCyte Inc.,of Cambridge, Mass. That company's chairman and CEO, molecularpharmacologist Christopher Mirabelli, told BioWorld Today: "Wehave submitted a joint patent application between ourselves and DanaFarber around the therapeutic utilities of the interaction between thechemokine receptors and gp120 and CD4. It covers essentially someinsights that we've made through working with Joe."
Mirabelli added: "We're trying to identify points of intervention fortherapies, be they small molecule antagonists or a blockingmonoclonal antibody." This drug-discovery strategy, he explained,"would render the receptor no longer visible, or available, for thehidden epitope that's created" to bind CCR-5.
Concurrent with Sodroski's paper in today's Nature, Mirabelli saidLeukocyte will collaborate with the Warner-Lambert Co. of MorrisPlains, N.J., to discover compounds that block the CCR-5 receptor."Besides AIDS drugs," he said, "it will target anti-inflammatorycompounds that work through that same chemokine receptor." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.