What activates AIDS? The body's immune reaction to HIV is a double-edged sword.

More than 2 decades after researchers identified the virus that muses AIDS, they're still struggling to understand it. How does it so successfully co-opt a person's immune system? Why do some people infected with the virus develop AIDS quickly and others not at all? Answers remain slow in coming, at least in part bemuse the course of the infection can't be predicted by any single attribute of a person's immune system or the causative agent--the human immunodeficiency vires, or HIV. Recently, however, researchers have suggested that a natural process called immune activation may determine why infection with HIV progresses differently in different people.

Immune activation occurs whenever immune system cells detect foreign invaders and send out chemical signals to draw other cells into the fight. It occurs at the beginning of any infection and, in the case of HIV, seems to remain engaged throughout. Researchers speculate that HW turns this normally beneficial response to bad effect.

Since the early days of AIDS, scientists have realized that a higher-than-normal proportion of immune cells becomes and stays activated in a person with HIV than in someone responding to another infection. Ironically, activation makes immune cells more vulnerable to the infection. That's because when immune cells are dividing, HIV can hijack their cellular machinery to copy viral genes.

"Modifying immune activation seems to be key to controlling viral replication," says Ronald Veazey of the Tulane Regional Primate Center in Covington, La.

According to recent findings, however, there's more to immune activation than simply providing a place for HIV to replicate. Especially high activation of the immune system in AIDS patients seems to correlate with poor outcomes. With a better understanding of the immune response, these intriguing results might offer new directions for therapy and vaccines.

MONKEY BUSINESS The ancestor of HIV was probably a virus that infected chimpanzees or African monkeys called sooty mangabeys and somehow jumped into people in the mid-1900s. Some sooty mangabeys in the wild are still infected with the simian version of HIV, called SIV, but the disease doesn't typically kill them. The disease seems to be benign in chimpanzees, too.

Unlike other monkeys infected with SIV--and people infected with HIV--sooty mangabeys and chimps can have high concentrations of an immunodeficiency vires circulating in their blood without suffering the immune system damage that leads to opportunistic infections and death. Typically, scientists follow immune system decline by measuring the blood concentrations of the specific type of immune cell, called CD4 T cells, that is targeted by HIV.

"What's different about mangabeys that explains why they don't progress to AIDS?" asks Mark Feinberg, an immunologist at the Yerkes Regional Primate Research Center at Emory University in Atlanta. To answer this question, scientists have looked at the more common sooty mangabeys rather than the endangered chimps.

It turns out that sooty mangabeys, despite high concentrations of SIV circulating in their blood, have little immune activation, says Feinberg. In contrast, rhesus macaques infected with SIV mount a vigorous immune response but eventually lose immune function and die.

"From the earliest days of infection, there are very diverse reactions in the different hosts" that SIV infects, says Feinberg. Despite sky-high concentrations of the vires, sooty mangabeys show few signs of immune activation and don't lose their CD4 T cells as macaques do, he reported at the 9th Conference on Retroviruses and Opportunistic Infections held in Seattle in February.

Because researchers control exactly when a lab animal is infected with vires, they can easily study very early steps in a monkey's immune response. We're finding [in macaques] that the intestine is a major initial site for viral replication, probably because immune cells are highly activated there," says Veazey. Immune cells in the gut, lungs, and reproductive tract are especially active because of their exposure to foreign proteins and antigens.

Veazey and his colleagues have begun studying the responses of individual macaques to see if the research can identify factors that are linked to progression to AIDS. In all the macaques studied so far, he says, CD4 T cells in the gut respond to SIV infection and are wiped out quickly. After that, however, different animals seem to have slightly different immune responses to the vires. Over several months, macaques with high immune activation, as measured by concentrations of certain chemicals in blood samples, have higher amounts of vires in their blood. In contrast, individuals with less immune activation go on to have lower vires concentrations.

Veazey and his colleagues haven't yet studied the macaques long enough to determine whether monkeys with lower immune activation fare better over the long term and whether, as in the sooty mangabeys, lower immune activation helps sidestep the most deadly aspects of infection.

TURNING TO PEOPLE Generally during the course of HIV infection, the higher a person's viral load--the amount of virus found in a blood sample--the worse that person will fare. That's probably because higher concentrations of the virus tend to be associated with lower numbers of CD4 T cells, which correlate with a poor prognosis.

There's emerging evidence that HIV-infected people with low immune activation may fare better than people with high immune activation do. Scientists reported some of these findings at the February meeting. These reports fit better with the new findings in monkeys than with previous observations in people.

In fact, researchers are still trying to understand how to reconcile this emerging evidence with the past observation that people who have been infected with HIV for long periods with no signs of developing AIDS actually have stronger-than-normal immune responses, including immune activation, against HIV.

Among 20 patients recently infected with HIV, those who had the least immune activation had lowest viral loads in the years following infection, reported William A. Blattner of the University of Maryland's Institute of Human Virology in Baltimore. "Effective host responses may counteract virus-induced immune activation during early infection and improve host capacity to control virus expression," he says. "It is clear from our work and the work of others that the ability of the host to effectively clear infection is vital to subsequent long-term survival"

Other findings suggesting an advantage from lowered immune activation come from studies of people infected with strains of HW that keep replicating vigorously despite drug treatment. Researchers have found that such patients--many of whom have been treated for long periods--fare much better than the scientists expect. "In our clinic, it was quite clear that these patients were not achieving complete suppression of the virus but were still doing quite well," says Steven Decks of San Francisco General Hospital.

It's not that the drugs are working better than expected, he says, but that somehow the drug-resistant virus is less damaging to these patients than normal HIV is to other patients with similar viral loads. The explanation, according to a report in the Feb. 1 Journal of Infectious Diseases, is that patients with the drug-resistant virus experience less immune activation than do patients with the same viral load of normal HIV.

"Some mutation in the drug-resistant virus diminishes [immune] activation,' speculates Decks, "but the mechanism is completely unknown"

A study of just four European patients, reported at the Seattle meeting by Frank Miedema of the University of Amsterdam and his colleagues, seems to confirm that low immune activation is playing a role in the preservation of immune function. These HIV-infected patients had high numbers of CD4 T cells despite increasing replication of drug-resistant virus in their blood. Low immune activation corresponded with preservation of immune function in the patients, said Miedema.

Additional evidence for the effect of immune activation on the progression of AIDS comes from studies of people, mostly in Africa, infected with a less-aggressive variant of HIV called HIV-2. These people seem to have less immune activation and a better prognosis than do people infected with HIV-1, the strain of the virus that's the main source of infection in the United States and most of the world.

HIV-2 infection is "nature's experiment" with a milder form of HIV disease, says Zvi Grossman of Tel-Aviv University in Israel, who's teamed up with Ana Sousa of the University of Lisbon Medical Center to study the role of immune activation in AIDS. Even though HIV-2 replicates more slowly in the body than HIV-1 does, an HIV-2 infection can gradually provoke strong immune activation that appears to be just as damaging long-term as the immune activation triggered by HIV-1, Grossman says.

Grossman, Sousa, and their colleagues recently showed that if people infected with HIV-1 and HIV-2 experience similar amounts of immune activation, their blood concentrations of CD4 T cells are reduced by about the same amount, though the HIV-2 carriers have much lower viral loads.

STILL NO CLEAR ANSWERS The links between immune activation and AIDS seem to be solid, says Decks. That's especially important because no drug therapy devised so far can wipe out an HIV infection, and a vaccine able to completely prevent it is unlikely, he adds. Understanding how HIV and a patient's immune system interact could lead to measures to help infected people live with the virus. Tracking immune activation might someday help doctors decide when to start, stop, and switch drug therapies, Deeks says.

However, the researchers all caution that the overall picture of immune activation is still difficult to make out. For example, if reducing immune activation during the first stages of infection improves survival, why do known long-term survivors of HIV have higher-than-normal overall immune responses to the virus?

Furthermore, animal studies demonstrate the difficulty of interfering with the immune system's delicate balance. At the Seattle meeting, Feinberg and his colleagues reported injecting four macaques with antibodies that blocked some aspects of immune activation. When the researchers then infected the monkeys with SIV, three developed AIDS, as marked by impaired immune system function and opportunistic infections. In contrast, in another four monkeys not treated with the antibodies and then injected with SIV, just one developed symptoms of AIDS. The researchers conclude that interfering with immune activation in this fashion didn't increase survival and may even have reduced it.

"It's a risky business to block immune response to HIV as a therapeutic measure,' notes William Paul of the National Institute of Allergy and Infectious Diseases in Bethesda, Md. "These animals are still infected, and infection is a bad thing."

Veazey believes that therapeutically interfering with immune activation is possible, but he cautions that "there's a very fine balance." If a treatment completely blocked the immune system from responding to infections, it would cause the same problem that AIDS does.

Some aspects of immune activation seem to benefit the host and others the virus, says Grossman. The difficulty of separating the two categories means that people should be extra cautious with therapies now being designed to strengthen a patient's immune response against HIV, he says. "Both reasoning and data suggest that this may occur at the price of enhancing HIV replication," he says.

When it comes to AIDS research, it seems, definite answers are as elusive as the virus itself.