In order to break, enter and infect its target cells, the AIDS virusneeds all the help it can get.
Its first accomplice is a receptor protein, CD4, which studs thesurface of the immune system's T lymphocytes _ HIV-1's primeprey _ and of macrophages, the virus' secondary cellular bull's-eye.
Once unsafe sex or narcotic-needle-sharing or an accident releases adollop of HIV-1 into its victim's bloodstream, a virus particle sidlesup to a hapless T-cell, and latches onto its CD4 docking site. Thenglycoproteins of the virion's envelope attach to the target cell's outermembrane.
When these two membranes make this contact, the next step is forthem to fuse or merge into a single layer, through which the predatoryvirus can penetrate the cell and hijack its replication and transmissionmachinery.
But that fusion step calls for a second co-conspirator.
Scientists at the National Institute of Allergy and Infectious Diseases(NIAID), led by molecular virologist Edward Berger, announcedonly six weeks ago in Science dated May 10 that they had discoveredthis cofactor. Because it permitted that fusion to take place, theynamed this new accessory to the fact "fusin." (See BioWorld Today,May 13, 1996, p. 1.)
Now, in next week's issue of Science, to be dated June 28, the sameNIAID group reports yet another fusion-facilitating co-factor, CKR5.Their paper will bear the title: "CC CKR5: a RANTS, MIP-1a, MIP-1b receptor as a fusion cofactor for macrophage-tropic HIV-1."
But this time, Berger and his co-authors are not alone in unmaskinganother hither-to-unknown member of the viral gang.
Yesterday's Nature, dated June 20, 1996, carries two papers back-to-back reporting the self-same discovery, almost in so many words.They are from separate laboratories at the Aaron Diamond AIDSResearch Center (ADARC) in New York City, an affiliate ofRockefeller University.
One co-author of the first Nature article is Paul Maddon, CEO ofProgenics Pharmaceuticals Inc. in Tarrytown, N.Y, a long-timehands-on research collaborator of ADARC. That paper's title reads:"HIV-1 entry into CD4+ cells is mediated by the chemokine receptorCC-CKR-5." The adjacent Nature paper reports, "Identification of amajor co-receptor for primary isolates of HIV-1."
Simultaneous Disclosure In RIval Journals
Having learned a week ago of Nature's imminentcoming-out party for CC-CKR5, Science lifted the media embargo onits own June 28 debut of the second HIV-1 cofactor.
"CC" stands for a pair of cysteine amino acids. Its discoverers referto the cofactor as CKR5 for short. It belongs to the same gene familyas fusin.
It turns out that fusin helps certain HIV-1 strains fuse with target Tcells, whereas CKR5 does the same inside job for viral isolates thatmove in on macrophages. But a trio of the immunity-policing b-chemokines, named RANTS, MIP-1a and MIP-1b _ which attract Tcells and macrophages to sites of inflammation _ recognize thecofactor as their receptor, and can act to block it and nab it on amacrophage's doorstep.
This foils the designs of the macrophage-programmed virus, the typemost commonly found in infected people. HIV-positive patients whodo not progress to outright AIDS over time have higher levels of b-chemokines in their blood. Paradoxically, individuals repeatedlyexposed to viral transmission, as by sexual activity with infectedpartners, have even higher levels of the b-chemokines. Progenics andADARC scientists found that CD4-positive cells from suchindividuals have a genetic defect, which presumably prevents thatsecond cofactor from doing its fusion thing.
As for fusin, it aids and abets fusion by laboratory-cultured strains ofHIV-1, but not by isolates from infected patients.
David Ho, scientific director of ADARC, observed: "Fusin isimportant as the receptor for aggressive HIV-1 variants thatsometimes, but not invariably, kill people more quickly than theviruses using CKR5. "
Ho pointed out: "Knowing that CKR5 plays a key role in the entry ofHIV-1 into immune cells will help researchers to develop new drugsfor HIV infection and AIDS, which may stop replication of thevirus."
Progenics Ratchets Up Drug DIscovery
ADARC's close industrial partner, Maddon of Progenics, toldBioWorld Today: "We fully intend to go down the path of drugdevelopment, trying to develop a product or products that mightinhibit the virus at the fusion step."
He described Progenics' line of investigation as "identifying theprecise molecular nature of what the second cofactor opens up. Theability to make therapeutics, which can take the shape of proteins,antibodies, small-molecular-weight molecules _ the whole spectrumof agents that can act on a given proteinaceous target."
Maddon recalled, "I'm the person who cloned CD4 back in the1980s, and who discovered this paradox that something else isneeded for fusion. Ten years have gone by, as we've worked veryhard in the fusion area, and there's been very little progress _ untilnow."
An editorial in Nature commented: "There is now a possibility ofdeveloping transgenic animals for HIV infection that express bothhuman CD4 and the relevant co-receptor." And Ho surmised: "Otherreceptors, yet unidentified, may also be involved in the entry of HIV-1 into CD4-positive cells." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.