1. Africa's victory, Africa's sorrow

2. A tough challenge

3.Multiple proteins

4. Immune-system helper

5. Making sense of vaccines

Protein 5-helix blocks HIV from entering a cell. 1. Two proteins, gp120 and gp 41, on the outside of a HIV particle. 2. When an immune cell nears, gp41 propels a part of itself into the host cell. 3. The immune cell is hooked and reeled in toward HIV. 4. The viral and cell membranes fuse, and the cell becomes infected.
Courtesy: Whitehead Institute for Biomedical Research

After all, HIV only multiplies inside immune cells.

About six years ago, researchers found that HIV connects to two receptors on a human cell. The finding accelerated the race to design molecules to stymie the essential fusion between virus and cell. 5-helix, the latest molecule to block the entry, comes from the lab of Peter Kim at the Whitehead Institute for Biomedical Research in Cambridge, Mass. The research was done with human cells in culture.

HIV's outer coat contains two associated proteins, poetically named gp120 and gp41. While much early vaccine research focused on gp120, it's now clear that it's gp41 that "harpoons" an immune-system cell bearing the two necessary receptors.

The gp41 then changes shape, causing the virus to merge with the immune cell so the viral RNA can enter the cell and copy itself.

Keep out!
The Kim experiment used viruses engineered to represent many HIV strains on the outside, says Michael Root, a molecular biologist and biophysicist who described the work in Science (see "Protein Design..." in the bibliography).

5-helix, Root says, "Binds gp41, preventing it from inducing the virus-cell merger." Root says the goal now is to test the protein in animals. If it proves safe and effective, he foresees using the protein as "salvage therapy" if other drugs fail.

While protease inhibitors have been a godsend against AIDS, they can cause unacceptable side effects, and the virus may also mutate to escape control by the inhibitors.

Both circumstances have "stimulated the search for new targets that could become sites of action for antiviral drugs," says Root. Preventing entry is one obvious tactic that 5-helix, and similar molecules could use for patients who can no longer benefit from protease inhibitors.

Because 5-helix, like insulin, is a protein, it would need to be injected. And let's say out loud that 5-helix is years from any human tests, as it's only been tested in a lab dish.

If all goes well with 5-helix, it could also become the basis for a vaccine, Kim told Science (see "HIV Inhibitor... " in the bibliography). While similar "antibody" therapies have failed because HIV comes in so many varieties, Kim, who is now research and development director at Merck, the pharmaceutical giant, says the region blocked by 5-helix does not vary much in HIV.

Helping the surviving immune system
Could AIDS drugs work without attacking HIV? Perhaps. Remember, AIDS is a two-step disease. First HIV infects, damaging the body's ability to destroy pathogens. Only then can "opportunistic infections" like tuberculosis actually cause illness and death.

Now, from the Wild West, comes an approach that ignores the virus and tries to help the immune system destroy opportunistic infections.

The work grew from research by John Marchalonis of the University of Arizona, who isolated a peptide (protein fragment) that the body seems to use to balance the activity of cells in the immune system. Specifically, the peptide seems to regulate a certain group of T-helper cells that are over-stimulated in the fight against HIV.

Too much stimulation leads to the death of the T-cells, leaving the body defenseless against infection. The peptide down-regulates the cells, resulting in what Marchalonis called (in a press release) "a gentle, well-tolerated therapy."
These protease inhibitors represent the first major advance against AIDS -- but they can have nasty side effects.

The peptide is not intended to prevent infection. Instead, Marchalonis said, "This is a way to maintain a normal T-cell immune system in someone who is HIV-positive."

In mouse experiments, the peptide preserved more than 80 percent of immune function after infection with an AIDS-like retrovirus. The remaining immunity was enough to resist Cryptosporidium, an intestinal parasite common among AIDS patients and others with damaged immune systems.

Magic shots?
The peptide must be injected, but Ronald Watson, professor of public health at University of Arizona, says it's "like magic, one or two injections are enough to slow the decline of the immune system."

Watson, who worked on the mouse experiments with the retrovirus, stresses that the peptide does not attack HIV. "It does extend the quality of life of the mouse, extends the time before the immune system crashes." In some studies, he says, "The mice live as long as the study goes on."

The peptide is now in safety trials with about 18 AIDS patients in San Francisco under the direction of Allergene, a California biotech firm. The trial is designed to establish safety, says Watson, and will probably be too small to prove benefits.

However, if the peptide works, it might also work against aging or illnesses marked by immune-system declines, Watson adds.

The peptide could have advantages over the traditional strategy of attacking the wily, fast-mutating HIV. While no AIDS researcher would discount the risk posed by rapid mutation of the virus, Watson says, "We are blocking the hyperstimulation of a particular subset of T-helper cells, so even if HIV mutates slightly, it's likely to still stimulate the same subset of cells."

In theory, he says, the peptide should continue to work -- unless HIV mutates severely enough to stimulate different T-helper cells.

Where do we go from here?