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AIDS Research: New Hope in HIV Disease

Science  20 Dec 1996:
Vol. 274, Issue 5295, pp. 1988
DOI: 10.1126/science.274.5295.1988

Potent new drugs and new insight into how HIV infects cells mark a turning point in the battle against HIV

What a difference a year can make. Just 12 months ago, AIDS was considered a death sentence, and those seeking to treat it seldom uttered the words “AIDS” and “hope” in the same sentence. Today, those terms have become inextricably linked in the minds and hearts of researchers and patients alike. And while the new optimism must be tempered with numerous caveats, the past year has ushered in a series of stunning breakthroughs, both in AIDS treatment and in basic research on HIV, the virus that causes the disease.

On the therapeutic side, new drugs called protease inhibitors—the fruits of years of work by armies of pharmaceutical company scientists—can now dramatically reduce HIV levels in the blood when taken with other antiviral compounds. At the same time, natural weapons in the immune system's defenses, polypeptide molecules called chemokines, have been unveiled as potent foes of HIV. To enter cells, the virus must bind to cell surface proteins that normally serve as receptors for the chemokines—and people born with defective receptors are immune to HIV infection. This work offers new insight into the pathogenesis of the disease and may one day blossom into new treatments or even vaccines (see p. 2005).

And so although AIDS remains a scourge of our era, especially in the developing world, 1996 marks a turning point in the frustrating 15-year battle against the disease, because both protease inhibitors and chemokines have a profound ability to block HIV replication. On the premise that any enemies of HIV are friends to humanity, we honor these twin discoveries as the 1996 Breakthrough of the Year.

These breakthroughs are the payoff of more than a decade of painstaking research into the life cycle of the AIDS virus. To wreak its deadly havoc, HIV must first attach to a target cell and inject its genetic material, in the form of RNA, into the cell cytoplasm. The viral RNA is transcribed into DNA via an enzyme called reverse transcriptase and then integrated into the cell's chromosomes, thus hijacking the cell's genetic machinery to make new viral RNA and proteins. But before these proteins can be assembled into new progeny viruses, they must first be clipped to their proper sizes by an enzyme called a protease.

Until this year, the only way to interrupt this process was to inhibit reverse transcriptase, as AZT and similar drugs do. But over time HIV learns to dodge this single bullet, developing resistance to the drugs. What was needed was a molecule that struck at another phase of the viral life cycle.

Enter the protease inhibitors, which jam the active site of the protease. But a number of hurdles had to be overcome to bring these drugs to market. Once the detailed three-dimensional structure of the protease was identified, scientists pored over drug-design computer programs for years before creating compounds which could be taken orally with few side effects and yet were still powerful enough to block the enzymatic site. Finally, in December 1995, the U.S. Food and Drug Administration (FDA) approved the first protease inhibitor for therapeutic use, saquinavir; two others, ritonavir and indinavir, quickly followed in March 1996. Studies have shown that in a majority of subjects, a protease inhibitor taken as a “triple therapy” cocktail with two inhibitors of reverse transcriptase can reduce blood concentrations of HIV to undetectable levels. This is indeed a major victory—one almost undreamt of a few years ago—because another study this year showed that patients with a lower “viral load” progress to AIDS much more slowly.

Open, sesame.

HIV uses chemokine receptors like CXCR4 to enter T cells.

Illustration: K. SUTLIFF

Just when the protease inhibitors were transforming the AIDS clinical world, the chemokines—small proteins involved in inflammatory responses—rocketed from relative obscurity to fame among basic researchers, as scientists grappling with two seemingly unrelated riddles of HIV infection converged on these molecules. The first line of research sought to explain how a small number of HIV-infected people could harbor the virus for years without getting sick. A team at the University of California, San Francisco, suggested that the so-called CD8 white blood cells in many of these patients produced a factor that could suppress HIV replication, but they couldn't isolate the substance.

The second mystery involved how HIV infects cells. Researchers had known for more than a decade that the virus must bind to a particular cell surface protein, called CD4, before it can enter target cells. But CD4 alone was not sufficient for entry, and dozens of labs had been engaged in a frustrating hunt for a second receptor.

On 15 December 1995, just 9 days after the FDA approved the first protease inhibitor, a paper by researchers from the U.S. National Cancer Institute and the San Raffaele Scientific Institute in Milan, Italy, claimed to identify the mysterious anti-HIV factor. The elusive molecule, the team said, was actually three related chemokines that worked in concert to suppress the virus. The news flashed across the AIDS research landscape like a flare lighting the night sky, because several chemokine receptors had recently been identified, although no one had connected them to HIV. Now it became clear that the two riddles might be linked: One of the chemokine receptors could be the long-sought second receptor for HIV, and the chemokines themselves might suppress the virus by blocking the binding site.

The results sent AIDS researchers chasing after chemokines and their receptors, and unleashed a flurry of new lab work. In a few months, this stampede turned into a roundup: During 2 weeks in June, five teams publishing in three journals branded a chemokine receptor called CCR5 as the co-receptor for HIV strains that predominate in early stages of infection, a finding that fits well with work by U.S. and Belgian teams showing that people with defective CCR5 receptors cannot be infected with HIV. What's more, just a few weeks earlier, researchers at the U.S. National Institutes of Health identified another protein they named fusin (now called CXCR4) as the co-receptor for HIV strains that appear to dominate during later stages of infection. And the molecule that naturally binds to CXCR4 also turned out to be a chemokine.

With these new insights, drug designers have once again shifted into high gear, and a number of laboratories and companies are scrambling to develop modified versions of chemokines that might block the receptors from viral attack—without triggering the panoply of inflammatory reactions that natural chemokines normally activate. Other options are therapies, including vaccines, that might spur chemokine-producing cells to pump out enough of these molecules to keep HIV at bay.

Despite the promise of the chemokines and the dramatic effects of the protease inhibitors, neither one can be considered the “magic bullet” that could vanquish HIV entirely. Indeed, it's an open question as to whether any drug could actually roust the virus from its many hiding places in the body. For example, the currently approved protease inhibitors cause mild to severe side effects and don't easily cross the blood-brain barrier, although that flaw could be corrected in new versions of these drugs.

But one problem that scientists alone cannot solve is the issue of access to the new therapies. The World Health Organization's statistics indicate that more than 90% of the 22.6 million HIV-infected people live in developing countries, and most of them lack access even to AZT, let alone the expensive triple therapy. Even in the United States, where the new therapies cost an estimated $12,000-plus per year, only a small minority of HIV-infected individuals currently receive them. So although researchers have added promising new weapons to the fight against AIDS, it's up to policy-makers to see that the fruits of these scientific labors are available to all.

ADDITIONAL READING

News Stories:

  • M. Balter, “Elusive HIV-Suppressor Factors Found,” Science, 8 December 1995, p. 1560.

  • M. Balter, “A Second Coreceptor for HIV in Early Stages of Infection,” Science, 21 June 1996, p. 1740.

  • J. Cohen, “Investigators Detail HIV's Fatal Handshake,” Science, 25 October 1996, p. 502.

  • J. Cohen, “Receptor Mutations Help Slow Disease Progression,” Science, 27 September 1996, p. 1797.

Special Report:

  • “The New Face of AIDS,” Science, 28 June 1996, p. 1876.

Research Papers:

  • F. Cocchi et al., “Identification of RANTES, MIP-1α, and MIP-1β as the Major HIV-Suppressive Factors Produced by CD8+ T Cells,” Science, 15 December 1995, p. 1811.

  • M. Dean et al., “Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene,” Science, 27 September 1996, p. 1856.

  • C. K. Lapham et al., “Evidence for Cell-Surface Association Between Fusin and the CD4-gp 120 Complex in Human Cell Lines,” Science, 25 October 1996, p. 602.

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