DURHAM, N.C. -- In its breaking-and-entering strategy, theAIDS virus has two accomplices. One, the CD4 receptor on thesurface of white blood cells, has been on researchers' "most-wanted" list for half a decade and is the centerpiece of severalongoing clinical trials. The other, a little -- and little-known --viral-envelope protein loop called V3 is just now surfacing.

In today's issue of Science, molecular biologists at the Centerfor AIDS Research at the Duke University School of Medicinefinger the envelope V3 loop as "a key regulatory component"rather than "merely a passive participant in the directinteraction of CD4 with the HIV-1 envelope.

When an invading virus enters the bloodstream, it headsstraight for T lymphocytes and macrophages, which are theprincipal white blood cells carrying the CD4 receptorprotruding through their surface membrane. As Bryan R.Cullen, who directs molecular biology at Duke's AIDS researchcenter here explained, "Once the virus binds CD4 on its surface,it starts a cascade of activating conformational changesmanaged by the V3 loop. The CD4 receptor supplies the "key,"or "password," to gain the virus entry into the specific T cells ormacrophages by which it cripples the body's immune system.

"Having found its appropriate target," Cullen continued, "it mustfuse with the cell, and V3 makes this happen; we don't knowhow -- yet. CD4 is necessary, but not sufficient; it lackssomething else. It's like two locks on one door. Once that door isopen, then another viral surface protein, gp 41, does the actualfusion job."

AIDS researchers, seeking to turn soluble CD4 into atherapeutic HIV bait, have been working with recombinantanalogs of the receptor. By flooding the bloodstream with thesesoluble decoy CD4s, (sCD4), they aim to lure, capture andneutralize the HIV virions before they reach the CD4-studded Tcells.

But as Cullen told BioWorld, in the early, asymptomatic stagesof an AIDS infection, CD4-covered macrophages rather than Tcells offer the main viral attraction, or tropism. One nub of histeam's research is determining which CD4-bearing cells aresusceptible. In the laboratory for the past five years or so,workers found that helper T cells seduced their in vitro virusesmore effectively than macrophages.

But in vivo, using native viral stocks from activated humanperipheral blood rather than viral isolates cultivated in the labover many generations, the Duke scientists found that thenative viral strains were pre-programmed to huntmacrophages in preference to T cells.

Because of this "difference between patient virus and labvirus," Biogen is discontinuing its sCD4 clinical trials, Biogen'sdirector of molecular biology, Richard A. Fisher, told BioWorld.

Cullen's Science study suggests that "during the initial, acuteinfection (stage), ... treatment with sCD4 would be likely toselectively suppress the replication of these T cell tropicvariants." If as the disease progresses, the T cell-hungryversion of HIV-1 becomes more prevalent, "then sCD4 mightprove clinically useful."

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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