First of all, HIV is "not a virus, it's a whole swarm of viruses," Lalezari says. A high error rate in replication gives rise to what Lalezari calls "a tremendous heterogeneity -- far greater than any other virus we encounter. Chicken pox is chicken pox. With HIV, there are as many strains as one can imagine."

Then there's the fact that, unlike, say, hepatitis viruses, which must reach the liver, HIV has its target cells waiting right there for it in the bloodstream, and those target cells are the very ones responsible for directing antiviral surveillance -- T-helper cells.

"With other viruses, you're hoping to prevent the development of disease, not the establishment of an infection per se," says Lalezari. "With HIV, you have to prevent the infection -- once the virus gets inside the cell, it's protected. And there is no vaccine for any virus that prevents infection."

That hasn't kept researchers from trying. Several scrappy biotech companies (see table below) and, with somewhat less urgency, the larger pharmaceutical houses have efforts in the HIV vaccine arena. For the most part, though, these products have proved more effective at stimulating antibody production, which usually does little good against a virus once it's inside the cell, than at triggering a strong cell-mediated response. As for clinical effects, vaccines oriented at prevention have struck out.

Farthest along clinically are The Immune Response Corp.'s Remune and VaxGen Inc.'s AIDSVAX. Oddly, the two vaccines are almost the diametrical opposites of one another. AIDSVAX is recombinant gp120, an HIV envelope protein. Remune is the whole killed virus, divested of a single element: gp120.

Asked about AIDSVAX, which is in Phase III trials, Lalezari simply says, "Nobody thinks that's going to work." Says Bruce Walker, professor of medicine at Harvard University, "VaxGen's product is unlikely to induce the kinds of cellular immune responses that we think are important, so I'm not particularly optimistic about that one." AIDSVAX appears more adept at arousing antibodies than killer T-cells.

The buzz on Remune is a little more upbeat. There's evidence that Remune can stimulate a several-fold -- or, in some cases, several hundred-fold -- proliferation of T-cells specific to core HIV antigens that are highly conserved across strains, which means it may be able to cope with HIV's variability.

"Remune got a lot of bad press early on because it was given to people who had high viral loads," says Harvard's Walker. The result was clinical failure. "What makes sense is to give the same vaccine to people whose viremia has been controlled by antiviral drugs."

Phase III trials of Remune as an immunotherapeutic, rather than a preventive, vaccine are underway in just under 700 patients on three continents in partnership with Agouron Pharmaceuticals Inc. (a Warner-Lambert company), says Ron Moss, Immune Response's vice president of medical and scientific affairs. The patients are simultaneously being treated with antiviral drugs. Final trial data are set to be reported on by the end of 2001, Moss says.

In another, smaller trial, Remune is being administered to patients on antivirals who then undergo several cycles of scheduled treatment interruptions, in the hope that the vaccine will prime their immune systems so that post-interruption increases in viral loads will be delayed. Immune Response's chief academic collaborator in this trial: Harvard's Bruce Walker.

By Bruce Goldman