Readers of this week's Science and Nature may be excused for thinking they're seeing double — if not quadruple.
Today's Nature, dated June 18, 1998, carries two related articles, both listing molecular virologist Joseph Sodroski as a principal author. One bears the title: "Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody."
The other paper's title: "The antigenic structure of the HIV gp120 envelope glycoprotein."
Tomorrow's Science, dated June 19, 1998, offers two more articles, titled "A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding," and "The HIV-1 envelope glycoproteins: Fusogens, antigens and immunogens."
Sodroski is a professor of pathology at Harvard Medical School, in Boston, and its affiliated Dana-Farber Cancer Institute. Late in 1996, he co-discovered the molecular co-conspirators by which the AIDS virus seizes, breaks and enters its target, infection-marked T cells in the human immune system. (See BioWorld Today, Nov. 14, 1996, p. 1.)
Since then, researchers have been flying blind in their efforts to turn this new finding to their advantage in devising better drugs and vaccines for fighting HIV-1 infection.
As of this week, with multiple publication of the virus's atomic structure, Sodroski told BioWorld Today, scientists have "a very clear picture of the gp120 protein. Before, we were blind; now we can see exactly what it looks like. The other thing it shows us is the defenses that the AIDS virus has evolved to help protect it from antibodies made by the human immune system."
Like Blind Men Palpating An Elephant
"Just as somebody who is sighted can do much better at penetrating the enemy's defense than somebody who's blind and just shooting randomly," Sodroski went on, "Knowing what those viral defenses look like will allow us to penetrate them in a more focussed way with drugs and vaccines."
As a four-part road map to the new findings revealed by solving the three-dimensional atomic structure of gp120, Sodroski summed up the substance of the four articles in the current Nature and Science:
"The primary paper is by Kwong et al. in Nature," he began. "That describes the structure of the gp120 viral envelope glycoprotein. It is part of the spikes studding the surface of the virus. They allow it to attach to the CD4 receptor on T cells, and to the chemokine co-receptors, in the context of how HIV enters cells. [Columbia University X-ray crystallographer Wayne Hendrickon is senior author.]
"The second Nature paper," Sodroski continued, "by Wyatt et al., describes gp120 as an antigen — how it triggers antibodies in its human targets, and how it protects itself from those antibodies. That's relevant particularly to gp120 as a vaccine component.
"The third paper, by Rizzutto et al. in Science, describes a highly conserved portion of gp120 that is important for attachment of the virus to CCR5, its chemokine receptor."
Sodroski described the fourth paper, by Wyatt and himself, also in Science, "as really just a review article on envelope glyoproteins in general," including allusion to its newfound structure.
A First: HIV Protein Crystal Structure Revealed
He and his co-authors have spent the last five years honing the gp120 molecule into a shape that could be crystalized, and its structure visualized by X-ray beams, to a fine resolution of 2.5 Angstroms. Their just published images capture the protein already bound to a fragment of its CD4 T cell target, and to an antibody that blocks chemokine-receptor binding.
That X-ray crystallography feat unmasked the AIDS virus as a wily and weighty foe of the human immune system. Sodroski counted the main ways:
"We can see at least three things from the structure," he said, "that are almost certainly part of those defenses. One is that there's a little bit of flexibility in this gp120 protein. It gives the virus an amazing capacity to change its shape, from the time it latches onto CD4 to the time it binds a chemokine receptor. And that means it's something of a moving target.
"The second thing is viral variability. HIV-1 does have variable regions that change from one strain to another. Those regions turn out to be pretty good at raising antibodies, but we don't really want to raise antibodies against the variable regions," Sodroski went on, "because those antibodies block only one or two strains of virus, and don't block strains that can change in those regions. So those types of antibodies aren't too interesting; they're like decoys.
"A third defense that we can now see is the sugar coating the virus spreads on the surface of its gp120 protein. Because sugars are made naturally in human bodies, and coat some of our own proteins, the immune system doesn't recognize sugars as foreign. So the virus can disguise that whole portion of gp120 by sugar-coating it."
Best Defense Is Offense — By Better AIDS Vaccines
These insights into the enemy's ploys against the human immune defenses should now sharpen countermeasures, particularly anti-HIV vaccines.
"Up to now," Sodroski observed, "the ability of HIV-1 gp120 to elicit the right kinds of desirable antibody responses has been very limited. It hasn't performed well as a vaccine candidate, which is probably why the virus has survived so well."
But as for novel vaccine candidates, he continued, "I think the only thing on the virus that antibodies can recognize is gp120. So we're stuck with using that one protein if we want to raise antibodies. But that suggests modifying gp120 to increase the exposure or stability of its more conserved — less variable — regions, to make a better vaccine candidate. By looking at this atomic structure, we have a very detailed blueprint now of what this protein looks like. We can perform these modifications with greater efficiency than we ever could in the past."
Several months ago, following the completion of the journal papers, Sodroski and his co-authors began "focussing most of our efforts on using the structure to form better vaccine candidates and design drugs that will interfere with HIV receptor binding."
He foresees that "as of next week, many groups in the world will be using this atomic structure to modify gp120 and improve its immunogenicity for new HIV vaccines." *